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fcb9b45c186e3eab9a54c930b17f890283c12a4b | wikidoc | Trimthoprim | Trimthoprim
Trimethoprim a common antibacterial agent with a half life of 8-11 hours, an unknown toxic dose or serum level. A toxic level will cause bone marrow depression, methemoglobinemia, and hyperkalemia. Trimethoprim acts to block synthesis of folic acid in bacteria by blocking the activity of the bacterial dihydrofolate reductase enzyme. Humans do not make their own folic acid, accounting for the selective toxicity of this agent against bacteria.
Trimethoprim has a bacteriostatic activity against a broad spectrum of pathogens.
Sulphonamides, the earliest class of antibacterial agents, block folic acid synthesis by acting on dihydropteroate synthase, the enzyme preceding dihydrofolate reductase in the pathway responsible for folic acid production. Trimethoprim was developed and marketed initially as a potentiator for sulphonamides. Co-trimoxazole is a combination of trimethoprim and the sulfonamide sulfamethoxazole. Since tetrahydrofolic acid synthesis is inhibited at two successive steps, the in vitro antibacterial effect of co-trimoxazole is better than that of the individual components. This synergy is more difficult to demonstrate in vivo. Pathogens resistant to both sulphonamides and trimethoprim are infrequent and a bactericidal effect may occur.
Because of increasing levels of resistance to sulphonamides and the increased risk of side-effects when used in combination, particularly Stevens-Johnson syndrome, trimethoprim is most often used as a single agent in the United Kingdom. The use of co-trimoxazole to treat bacteiral infections is no longer recommended in the UK. | Trimthoprim
Trimethoprim a common antibacterial agent with a half life of 8-11 hours, an unknown toxic dose or serum level. A toxic level will cause bone marrow depression, methemoglobinemia, and hyperkalemia. Trimethoprim acts to block synthesis of folic acid in bacteria by blocking the activity of the bacterial dihydrofolate reductase enzyme. Humans do not make their own folic acid, accounting for the selective toxicity of this agent against bacteria.
Trimethoprim has a bacteriostatic activity against a broad spectrum of pathogens.
Sulphonamides, the earliest class of antibacterial agents, block folic acid synthesis by acting on dihydropteroate synthase, the enzyme preceding dihydrofolate reductase in the pathway responsible for folic acid production. Trimethoprim was developed and marketed initially as a potentiator for sulphonamides. Co-trimoxazole is a combination of trimethoprim and the sulfonamide sulfamethoxazole. Since tetrahydrofolic acid synthesis is inhibited at two successive steps, the in vitro antibacterial effect of co-trimoxazole is better than that of the individual components. This synergy is more difficult to demonstrate in vivo. Pathogens resistant to both sulphonamides and trimethoprim are infrequent and a bactericidal effect may occur.[1]
Because of increasing levels of resistance to sulphonamides and the increased risk of side-effects when used in combination, particularly Stevens-Johnson syndrome, trimethoprim is most often used as a single agent in the United Kingdom. The use of co-trimoxazole to treat bacteiral infections is no longer recommended in the UK. | https://www.wikidoc.org/index.php/Trimthoprim | |
763683682a3d03e3747c50b13fd113f72f112344 | wikidoc | Trip sitter | Trip sitter
Trip sitter is a term used by recreational or spiritual drug users to describe a person who remains sober to ensure the safety of the drug user while he or she is under the influence of a drug; they are especially common with first-time experiences or when using psychedelics, dissociatives and deliriants. This practice can be qualified as a means of harm reduction.
Also called a Psychedelic Guide or Guide, this latter term is more often used to describe someone who takes an active role in guiding a drug user's experiences as opposed to a sitter who merely remains present, ready to discourage bad trips and handle emergencies but not otherwise getting involved. Guides are more common amongst spiritual users of entheogens. Psychedelic guides were strongly encouraged by Timothy Leary and the other authors of The Psychedelic Experience: A Manual Based on the Tibetan Book of the Dead.Template:Ref label Trip sitters are also mentioned in the Responsible Drug User's Oath.
Some sources recommend a sitter be present when certain drugs are used, regardless of the user's experience or comfort with the substance; for example, a sitter may be necessary for users of Salvia divinorum because the drug can sometimes cause both disorientation and a desire to move about before the effects have worn off.
Obviously, while the presence of a trip sitter or guide may make a drug user feel safer, it is no guarantee that a bad trip will not occur, or that the drug user will remain free of physical or mental harm.
# Who trip sits
In some cases, a trip sitter may be a medical professional, such as the nurses used in psychedelic research or a therapist who performs psychedelic psychotherapy. Sometimes, a drug user will pay another, more experienced user to sit for them. However, the most common trip sitter is a friend or family member whom the drug user trusts. Template:Ref label
Although an ideal sitter is one who is both personally experienced with the substance being used, as well as one trained to deal with any potential psychological or medical crisis that may arise, arguably the most important qualities may be the willingness to help, the responsibility needed to stay sober enough to be fully present, and the ability to be relaxed, accepting, and not interfere with the experience beyond the wishes of the user. A sitter should be willing to research the substance in question, and understand when to call for professional medical assistance.Template:Ref label
Especially when using a short-acting substance such as DMT or Salvia divinorum, it may be possible for two people to take turns, with one being the sitter while the other takes the psychedelic.
# Common duties
A responsible trip sitter assists a drug user before, during, and after their experience; it is their responsibility to help the user by making sure they drink enough water, assisting them in moving around when needed, and generally doing whatever necessary to ensure their comfort throughout the trip.Template:Ref label Template:Ref label
## Before use
The responsible trip sitter will thoroughly research the substance which will be ingested in order to answer all potential questions the user may have, and to prepare for any potential crisis situations it may cause. The sitter will discuss this research in detail with the user; it is also considered important to talk to the user about any ground rules for the session, how to handle any emergencies that may arise, and what, if any, guidance will be wanted during the trip.Template:Ref label Template:Ref label
A trip sitter will also frequently help a drug user create a healthy set and setting for the experience. They do this by making sure the user's surroundings are comfortable and orderly, adjusting lighting, temperature, and music (if any) to suit the desired tone of the trip, and overall doing whatever they can to maximize the user's openness to the experience and minimize their fear.Template:Ref label Template:Ref label Template:Ref label
## During the psychedelic experience
A sitter typically remains present for the entire experience. In some cases, they may actively guide the experience of the user by adjusting their environment or through guided meditation or visualization. In other cases, they stay uninvolved except when the user has questions, fears, or needs for which the sitter can provide (such as making sure the user drinks enough water). Assistance in facing fears may be especially necessary if the experience turns into a bad trip. Template:Ref label Template:Ref label Template:Ref label Template:Ref label Template:Ref label In order to maintain the immediate well-being of the drug user, it is important for the sitter to know what situations he can or cannot handle on his own, and when to call for professional medical assistance. Template:Ref label
Although the sitter may be called upon to intervene during a difficult situation, bad trip, or medical crisis, the mere presence of a caring sitter is often enough to keep a user comfortable and even enable deeper exploration of the drug's effects. Template:Ref label The experience of being present during an especially powerful experience, such as when the user reaches new insight into themselves or their beliefs about the nature of the universe, is reportedly quite rewarding. Template:Ref label
## After the trip
A sitter may help the drug user to integrate or understand their experiences when the experience is complete. Just as they did before, and during the trip, they may reassure the user about any fears or worries that have occurred. This discussion may take place immediately after the drug's effects have worn off, or they may wait until a later date. Template:Ref label Template:Ref label | Trip sitter
Trip sitter is a term used by recreational or spiritual drug users to describe a person who remains sober to ensure the safety of the drug user while he or she is under the influence of a drug; they are especially common with first-time experiences or when using psychedelics, dissociatives and deliriants. This practice can be qualified as a means of harm reduction.
Also called a Psychedelic Guide or Guide, this latter term is more often used to describe someone who takes an active role in guiding a drug user's experiences as opposed to a sitter who merely remains present, ready to discourage bad trips and handle emergencies but not otherwise getting involved. Guides are more common amongst spiritual users of entheogens. [1] [2] Psychedelic guides were strongly encouraged by Timothy Leary and the other authors of The Psychedelic Experience: A Manual Based on the Tibetan Book of the Dead.Template:Ref label Trip sitters are also mentioned in the Responsible Drug User's Oath.
Some sources recommend a sitter be present when certain drugs are used, regardless of the user's experience or comfort with the substance; for example, a sitter may be necessary for users of Salvia divinorum because the drug can sometimes cause both disorientation and a desire to move about before the effects have worn off. [3]
Obviously, while the presence of a trip sitter or guide may make a drug user feel safer, it is no guarantee that a bad trip will not occur, or that the drug user will remain free of physical or mental harm.
# Who trip sits
In some cases, a trip sitter may be a medical professional, such as the nurses used in psychedelic research or a therapist who performs psychedelic psychotherapy.[4] [5] Sometimes, a drug user will pay another, more experienced user to sit for them. However, the most common trip sitter is a friend or family member whom the drug user trusts. Template:Ref label
Although an ideal sitter is one who is both personally experienced with the substance being used, as well as one trained to deal with any potential psychological or medical crisis that may arise, arguably the most important qualities may be the willingness to help, the responsibility needed to stay sober enough to be fully present, and the ability to be relaxed, accepting, and not interfere with the experience beyond the wishes of the user. A sitter should be willing to research the substance in question, and understand when to call for professional medical assistance.Template:Ref label [6] [7]
Especially when using a short-acting substance such as DMT or Salvia divinorum, it may be possible for two people to take turns, with one being the sitter while the other takes the psychedelic.
# Common duties
A responsible trip sitter assists a drug user before, during, and after their experience; it is their responsibility to help the user by making sure they drink enough water, assisting them in moving around when needed, and generally doing whatever necessary to ensure their comfort throughout the trip.Template:Ref label Template:Ref label
## Before use
The responsible trip sitter will thoroughly research the substance which will be ingested in order to answer all potential questions the user may have, and to prepare for any potential crisis situations it may cause. The sitter will discuss this research in detail with the user; it is also considered important to talk to the user about any ground rules for the session, how to handle any emergencies that may arise, and what, if any, guidance will be wanted during the trip.Template:Ref label Template:Ref label
A trip sitter will also frequently help a drug user create a healthy set and setting for the experience. They do this by making sure the user's surroundings are comfortable and orderly, adjusting lighting, temperature, and music (if any) to suit the desired tone of the trip, and overall doing whatever they can to maximize the user's openness to the experience and minimize their fear.Template:Ref label Template:Ref label Template:Ref label
## During the psychedelic experience
A sitter typically remains present for the entire experience. In some cases, they may actively guide the experience of the user by adjusting their environment or through guided meditation or visualization. In other cases, they stay uninvolved except when the user has questions, fears, or needs for which the sitter can provide (such as making sure the user drinks enough water). Assistance in facing fears may be especially necessary if the experience turns into a bad trip. Template:Ref label Template:Ref label Template:Ref label Template:Ref label Template:Ref label In order to maintain the immediate well-being of the drug user, it is important for the sitter to know what situations he can or cannot handle on his own, and when to call for professional medical assistance. Template:Ref label
Although the sitter may be called upon to intervene during a difficult situation, bad trip, or medical crisis, the mere presence of a caring sitter is often enough to keep a user comfortable and even enable deeper exploration of the drug's effects. Template:Ref label The experience of being present during an especially powerful experience, such as when the user reaches new insight into themselves or their beliefs about the nature of the universe, is reportedly quite rewarding. Template:Ref label
## After the trip
A sitter may help the drug user to integrate or understand their experiences when the experience is complete. Just as they did before, and during the trip, they may reassure the user about any fears or worries that have occurred. This discussion may take place immediately after the drug's effects have worn off, or they may wait until a later date. Template:Ref label Template:Ref label | https://www.wikidoc.org/index.php/Trip_sitter | |
87588a9c122063764820a10c1d8fa9e67858911b | wikidoc | Trophoblast | Trophoblast
# Overview
Trophoblasts (from Greek threphein: to feed) are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg.
# Function
Trophoblasts are invasive, eroding, and metastasizing cells of the placenta.
Trophoblasts mediate the implantation of the embryo into the endometrium, but they are never incorporated into the mother's body or the fetus. They are not "fetal" cells.
Trophoblasts become inert during pregnancy and are completely rejected by the fetus and mother at delivery. They can be seen as the thin membrane covering the fetus at birth, the caul.
# Differentiation
The trophoblast proliferates and differentiates into 2 cell layers:
# Pathology
The invasion of a specific type of trophoblast (extravillous trophoblast) into the maternal uterus is a vital stage in the establishment of pregnancy:
- Failure of the trophoblast to invade sufficiently may be important in the development of some cases of pre-eclampsia.
- Too firm an attachment may lead to placenta accreta.
# Additional images
- Blastodermic vesicle of Vespertilio murinus.
- Section through embryonic disk of Vespertilio murinus.
- Transverse section of a chorionic villus.
- Scheme of placental circulation. | Trophoblast
Template:Infobox Embryology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Trophoblasts (from Greek threphein: to feed) are cells forming the outer layer of a blastocyst, which provide nutrients to the embryo and develop into a large part of the placenta. They are formed during the first stage of pregnancy and are the first cells to differentiate from the fertilized egg.
# Function
Trophoblasts are invasive, eroding, and metastasizing cells of the placenta.
Trophoblasts mediate the implantation of the embryo into the endometrium, but they are never incorporated into the mother's body or the fetus. They are not "fetal" cells.
Trophoblasts become inert during pregnancy and are completely rejected by the fetus and mother at delivery. They can be seen as the thin membrane covering the fetus at birth, the caul.[1]
# Differentiation
The trophoblast proliferates and differentiates into 2 cell layers:
# Pathology
The invasion of a specific type of trophoblast (extravillous trophoblast) into the maternal uterus is a vital stage in the establishment of pregnancy:
- Failure of the trophoblast to invade sufficiently may be important in the development of some cases of pre-eclampsia.
- Too firm an attachment may lead to placenta accreta.
# Additional images
- Blastodermic vesicle of Vespertilio murinus.
- Section through embryonic disk of Vespertilio murinus.
- Transverse section of a chorionic villus.
- Scheme of placental circulation. | https://www.wikidoc.org/index.php/Trophoblast | |
fd3f20a78fe9e9a70d69c62f4295cc3aaafcb8b1 | wikidoc | Tropomyosin | Tropomyosin
# Overview
Tropomyosin, along with troponin, regulates the shortening of the muscle protein filaments actin and myosin. In resting muscle fibres, tropomyosin is displaced from its normal binding groove by troponin. This displaced conformation of tropomyosin prevents the binding of myosin heads, thereby inhibiting muscle contraction. Under normal stimulation to muscle fibers, Ca2+ ions are released from the sarcoplasmic reticulum of the myocytes which causes troponin to release its hold on actin, allowing tropomyosin to return to a normal conformation which allows myosin heads to walk along actin filaments and thereby facilitating muscle contraction.
# Functional Characteristics
## Sliding filament theory
Tropomyosin is an alpha helical coiled coil protein dimer that binds end to end along F actin filaments in striated muscle. Tropomyosin blocks myosin binding and hence crossbridge cycling in the absence of Ca2+ and the muscle Ca2+ regulatory element troponin. Ca2+ influx from the sarcoplasmic reticulum of striated muscle myocytes binds to troponin and subsequently moves tropomyosin on the F-actin filament exposing the myosin binding sites.
Recent structural visualization and kinetic modeling has suggested that myosin binding further moves tropomyosin on actin to a fully open state allowing for uninhibited crossbridge cycling as the muscle contracts. This three state model of thin filament regulation involving tropomyosin and troponin is still debated by experts who believe that two state regulation of muscle contraction (involving a blocked and open state) is sufficient to explain current experimental data and models.
# Allergies
Tropomyosin is a pan-allergen (an allergen widely-distributed in the nature) because it is a highly-conserved protein among species. Certain tropomyosins are known to cause allergies in certain people, and those who have cross-reactive allergies can get symptons from a range of sources due to a common allergen found in all these sources: Shrimp, dust mites and mollusks. This common allergen is the reason why some people sensitized with mite tropomyosin could have an allergic reaction after eating seafood.
# Genes
- TPM1
- TPM2
- TPM3
- TPM4
# Additional images
- Molecular mechanisms of muscular function | Tropomyosin
# Overview
Tropomyosin, along with troponin, regulates the shortening of the muscle protein filaments actin and myosin. In resting muscle fibres, tropomyosin is displaced from its normal binding groove by troponin. This displaced conformation of tropomyosin prevents the binding of myosin heads, thereby inhibiting muscle contraction. Under normal stimulation to muscle fibers, Ca2+ ions are released from the sarcoplasmic reticulum of the myocytes which causes troponin to release its hold on actin, allowing tropomyosin to return to a normal conformation which allows myosin heads to walk along actin filaments and thereby facilitating muscle contraction.
# Functional Characteristics
## Sliding filament theory
Tropomyosin is an alpha helical coiled coil protein dimer that binds end to end along F actin filaments in striated muscle. Tropomyosin blocks myosin binding and hence crossbridge cycling in the absence of Ca2+ and the muscle Ca2+ regulatory element troponin. Ca2+ influx from the sarcoplasmic reticulum of striated muscle myocytes binds to troponin and subsequently moves tropomyosin on the F-actin filament exposing the myosin binding sites.
Recent structural visualization and kinetic modeling has suggested that myosin binding further moves tropomyosin on actin to a fully open state allowing for uninhibited crossbridge cycling as the muscle contracts. This three state model of thin filament regulation involving tropomyosin and troponin is still debated by experts who believe that two state regulation of muscle contraction (involving a blocked and open state) is sufficient to explain current experimental data and models.
# Allergies
Tropomyosin is a pan-allergen (an allergen widely-distributed in the nature) because it is a highly-conserved protein among species. Certain tropomyosins are known to cause allergies in certain people, and those who have cross-reactive allergies can get symptons from a range of sources due to a common allergen found in all these sources: Shrimp, dust mites and mollusks. This common allergen is the reason why some people sensitized with mite tropomyosin could have an allergic reaction after eating seafood.
# Genes
- TPM1
- TPM2
- TPM3
- TPM4
# Additional images
- Molecular mechanisms of muscular function
# External links
- Diagrams and explanations at biomol.uci.edu
de:Tropomyosin
it:Tropomiosina
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Tropomyosin | |
00e7eaeaacc98d49e6a24a089d6332cc21d15140 | wikidoc | Trypan Blue | Trypan Blue
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Trypan Blue is an Ophthalmologic agent that is FDA approved for the procedure of ophthalmic posterior surgery and facilitates removal of epiretinal tissue.. Common adverse reactions include discoloration of high water content hydrogen intraocular lenses and inadvertent staining of the posterior lens capsule and vitreous face.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- MembraneBlue™ 0.15% is indicated for use as an aid in ophthalmic surgery by staining the epiretinal membranes during ophthalmic surgical vitrectomy procedures, facilitating removal of the tissue.
# Dosage
- Make sure the plunger moves smoothly before use. Prime the syringe prior to use by retracting the plunger before injecting the fluid. Alternatively, twist the plunger into the stopper in a clockwise motion until tight. Once tight, continue turning the plunger in a clockwise motion until the stopper rotates freely within the syringe, two or three rotations. The syringe is now primed and suitable for injection.
- Before injection of MembraneBlue™ 0.15% perform a ‘fluid-air exchange’, i.e. filling the entire vitreous cavity with air, to prevent aqueous dilution of MembraneBlue™ 0.15%. MembraneBlue™ 0.15% is carefully applied to the retinal membrane using a blunt cannula attached to the MembraneBlue™ 0.15% syringe, without allowing the cannula to contact or damage the retina. Sufficient staining is expected on contact with the membrane. All excess dye should be removed from the vitreous cavity before performing an air-fluid exchange, to prevent unnecessary spreading of the dye.
- MembraneBlue™ 0.15% can also be injected directly in a BSS filled vitreous cavity (instead of injecting under air). Clinical use demonstrated that, after complete vitreous and posterior hyaloid removal, sufficient staining is achieved after 30 seconds of application under BSS.
- MembraneBlue™ 0.15% is intended to be applied directly on the areas where membranes could be present, staining any portion of the membrane which comes in contact with the dye. The dye does not penetrate the membrane.
# DOSAGE FORMS AND STRENGTH
- MembraneBlue™ 0.15% (trypan blue ophthalmic solution) is supplied in 2.25 mL syringes filled to a volume of 0.5 mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Trypan Blue in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trypan Blue in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- MembraneBlue™ 0.15% is indicated for use as an aid in ophthalmic surgery by staining the epiretinal membranes during ophthalmic surgical vitrectomy procedures, facilitating removal of the tissue.
# Dosage
- Make sure the plunger moves smoothly before use. Prime the syringe prior to use by retracting the plunger before injecting the fluid. Alternatively, twist the plunger into the stopper in a clockwise motion until tight. Once tight, continue turning the plunger in a clockwise motion until the stopper rotates freely within the syringe, two or three rotations. The syringe is now primed and suitable for injection.
- Before injection of MembraneBlue™ 0.15% perform a ‘fluid-air exchange’, i.e. filling the entire vitreous cavity with air, to prevent aqueous dilution of MembraneBlue™ 0.15%. MembraneBlue™ 0.15% is carefully applied to the retinal membrane using a blunt cannula attached to the MembraneBlue™ 0.15% syringe, without allowing the cannula to contact or damage the retina. Sufficient staining is expected on contact with the membrane. All excess dye should be removed from the vitreous cavity before performing an air-fluid exchange, to prevent unnecessary spreading of the dye.
- MembraneBlue™ 0.15% can also be injected directly in a BSS filled vitreous cavity (instead of injecting under air). Clinical use demonstrated that, after complete vitreous and posterior hyaloid removal, sufficient staining is achieved after 30 seconds of application under BSS.
- MembraneBlue™ 0.15% is intended to be applied directly on the areas where membranes could be present, staining any portion of the membrane which comes in contact with the dye. The dye does not penetrate the membrane.
# DOSAGE FORMS AND STRENGTH
- MembraneBlue™ 0.15% (trypan blue ophthalmic solution) is supplied in 2.25 mL syringes filled to a volume of 0.5 mL.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Trypan Blue in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trypan Blue in pediatric patients.
# Contraindications
- MembraneBlue™ 0.15% is contraindicated when a non-hydrated (dry state), hydrophilic acrylic intraocular lens (IOL) is planned to be inserted into the eye. The dye may be absorbed by the IOL and stain it.
# Warnings
Excessive staining:
- It is recommended that after injection all excess MembraneBlue™ 0.15% be immediately removed from the eye.
Priming of the syringe:
- Make sure the plunger moves smoothly before use: first retract the plunger or twist the plunger in a clockwise motion before injecting the fluid.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions reported following use of MembraneBlue™ 0.15% include discoloration of high water content hydrogen intraocular lenses and inadvertent staining of the posterior lens capsule and vitreous face. Staining of the posterior lens capsule or staining of the vitreous face is generally self limited, lasting up to one week.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Trypan Blue in the drug label.
# Drug Interactions
There is limited information regarding Trypan Blue Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Teratogenic Effects: Pregnancy Category C. Trypan blue is teratogenic in rats, mice, rabbits, hamsters, dogs, guinea pigs, pigs, and chickens. The majority of teratogenicity studies performed involve intravenous, intraperitoneal, or subcutaneous administration in the rat. The teratogenic dose is 50 mg/kg as a single dose or 25 mg/kg/day during embryogenesis in the rat. These doses are approximately 4,000- and 2,000-fold the maximum recommended human dose of 0.75 mg per injection based in a 60 kg person, assuming that the whole dose is completely absorbed. Characteristic anomalies included neural tube, cardiovascular, vertebral, tail, and eye defects. Trypan blue also caused an increase in post-implantation mortality, and decreased fetal weight. In the monkey, trypan blue caused abortions with single or two daily doses of 50 mg/kg between 20th to 25th days of pregnancy, but no apparent increase in birth defects (approximately 4,000-fold maximum recommended human dose of 0.75 mg per injection, assuming total absorption). There are no adequate and well-controlled studies in pregnant women. Trypan blue should be given to a pregnant woman only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trypan Blue in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trypan Blue during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when trypan blue is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of trypan blue have been established in pediatric patients. Use of trypan blue is supported by evidence from an adequate and well-controlled study in pediatric patients.
### Geriatic Use
- No overall differences in safety and effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Trypan Blue with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trypan Blue with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trypan Blue in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trypan Blue in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trypan Blue in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trypan Blue in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- There is limited information regarding Monitoring of Trypan Blue in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Trypan Blue in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Trypan Blue in the drug label.
# Pharmacology
## Mechanism of Action
- MembraneBlue™ 0.15% selectively stains membranes in the human eye during posterior surgery, such as epiretinal membranes (ERM) and Internal Limiting Membranes (ILM).
## Structure
- MembraneBlue™ 0.15% (trypan blue ophthalmic solution) is a sterile solution of trypan blue (an acid di-azo group dye). MembraneBlue™ 0.15% selectively stains epiretinal membranes during ophthalmic surgical vitrectomy procedures.
- Each mL of MembraneBlue™ 0.15% contains: 1.5 mg trypan blue; 1.9 mg sodium mono-hydrogen orthophosphate (Na2HPO4.2H2O); 0.3 mg sodium di-hydrogen orthophosphate (NaH2PO4.2H2O); 8.2 mg sodium chloride (NaCl); and water for injection. The pH is 7.3 - 7.6. The osmolality is 257-314 mOsm/kg.
- The drug substance trypan blue has the chemical name 3,3’- bis(5-amino-4-hydroxy-2,7-naphthalenedisulfonic acid) tetra sodium salt, a molecular weight of 960.8, a molecular formula of C34H24N6Na4O14S4, and has the following chemical structure:
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Trypan Blue in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Trypan Blue in the drug label.
## Nonclinical Toxicology
- Trypan blue is carcinogenic in rats. Wister/Lewis rats developed lymphomas after receiving subcutaneous injections of 1% trypan blue dosed at 50 mg/kg every other week for 52 weeks (total dose approximately 100,000-fold the maximum recommended human dose of 0.75 mg per injection in a 60 kg person, assuming total absorption).
- Trypan blue was mutagenic in the Ames test and caused DNA strand breaks in vitro.
# Clinical Studies
There is limited information regarding Clinical Studies of Trypan Blue in the drug label.
# How Supplied
- MembraneBlue™ 0.15% is supplied as follows:
- 0.5 mL of MembraneBlue™ 0.15% in a sterile single-use Luer Lok, 2.25 mL glass syringe, grey rubber plunger stopper and tip cap with polypropylene plunger rod in a peel pouch. Five pouched products are packed in one distribution box.
## Storage
- MembraneBlue™ 0.15% is stored at 15-25ºC (59-77ºF). Protect from direct sunlight.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Trypan Blue in the drug label.
# Precautions with Alcohol
- Alcohol-Trypan Blue interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MEMBRANEBLUE®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Trypan Blue
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Disclaimer
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# Overview
Trypan Blue is an Ophthalmologic agent that is FDA approved for the procedure of ophthalmic posterior surgery and facilitates removal of epiretinal tissue.. Common adverse reactions include discoloration of high water content hydrogen intraocular lenses and inadvertent staining of the posterior lens capsule and vitreous face.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- MembraneBlue™ 0.15% is indicated for use as an aid in ophthalmic surgery by staining the epiretinal membranes during ophthalmic surgical vitrectomy procedures, facilitating removal of the tissue.
# Dosage
- Make sure the plunger moves smoothly before use. Prime the syringe prior to use by retracting the plunger before injecting the fluid. Alternatively, twist the plunger into the stopper in a clockwise motion until tight. Once tight, continue turning the plunger in a clockwise motion until the stopper rotates freely within the syringe, two or three rotations. The syringe is now primed and suitable for injection.
- Before injection of MembraneBlue™ 0.15% perform a ‘fluid-air exchange’, i.e. filling the entire vitreous cavity with air, to prevent aqueous dilution of MembraneBlue™ 0.15%. MembraneBlue™ 0.15% is carefully applied to the retinal membrane using a blunt cannula attached to the MembraneBlue™ 0.15% syringe, without allowing the cannula to contact or damage the retina. Sufficient staining is expected on contact with the membrane. All excess dye should be removed from the vitreous cavity before performing an air-fluid exchange, to prevent unnecessary spreading of the dye.
- MembraneBlue™ 0.15% can also be injected directly in a BSS filled vitreous cavity (instead of injecting under air). Clinical use demonstrated that, after complete vitreous and posterior hyaloid removal, sufficient staining is achieved after 30 seconds of application under BSS.
- MembraneBlue™ 0.15% is intended to be applied directly on the areas where membranes could be present, staining any portion of the membrane which comes in contact with the dye. The dye does not penetrate the membrane.
# DOSAGE FORMS AND STRENGTH
- MembraneBlue™ 0.15% (trypan blue ophthalmic solution) is supplied in 2.25 mL syringes filled to a volume of 0.5 mL.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Trypan Blue in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trypan Blue in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
# Indications
- MembraneBlue™ 0.15% is indicated for use as an aid in ophthalmic surgery by staining the epiretinal membranes during ophthalmic surgical vitrectomy procedures, facilitating removal of the tissue.
# Dosage
- Make sure the plunger moves smoothly before use. Prime the syringe prior to use by retracting the plunger before injecting the fluid. Alternatively, twist the plunger into the stopper in a clockwise motion until tight. Once tight, continue turning the plunger in a clockwise motion until the stopper rotates freely within the syringe, two or three rotations. The syringe is now primed and suitable for injection.
- Before injection of MembraneBlue™ 0.15% perform a ‘fluid-air exchange’, i.e. filling the entire vitreous cavity with air, to prevent aqueous dilution of MembraneBlue™ 0.15%. MembraneBlue™ 0.15% is carefully applied to the retinal membrane using a blunt cannula attached to the MembraneBlue™ 0.15% syringe, without allowing the cannula to contact or damage the retina. Sufficient staining is expected on contact with the membrane. All excess dye should be removed from the vitreous cavity before performing an air-fluid exchange, to prevent unnecessary spreading of the dye.
- MembraneBlue™ 0.15% can also be injected directly in a BSS filled vitreous cavity (instead of injecting under air). Clinical use demonstrated that, after complete vitreous and posterior hyaloid removal, sufficient staining is achieved after 30 seconds of application under BSS.
- MembraneBlue™ 0.15% is intended to be applied directly on the areas where membranes could be present, staining any portion of the membrane which comes in contact with the dye. The dye does not penetrate the membrane.
# DOSAGE FORMS AND STRENGTH
- MembraneBlue™ 0.15% (trypan blue ophthalmic solution) is supplied in 2.25 mL syringes filled to a volume of 0.5 mL.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Trypan Blue in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Trypan Blue in pediatric patients.
# Contraindications
- MembraneBlue™ 0.15% is contraindicated when a non-hydrated (dry state), hydrophilic acrylic intraocular lens (IOL) is planned to be inserted into the eye. The dye may be absorbed by the IOL and stain it.
# Warnings
Excessive staining:
- It is recommended that after injection all excess MembraneBlue™ 0.15% be immediately removed from the eye.
Priming of the syringe:
- Make sure the plunger moves smoothly before use: first retract the plunger or twist the plunger in a clockwise motion before injecting the fluid.
# Adverse Reactions
## Clinical Trials Experience
- Adverse reactions reported following use of MembraneBlue™ 0.15% include discoloration of high water content hydrogen intraocular lenses and inadvertent staining of the posterior lens capsule and vitreous face. Staining of the posterior lens capsule or staining of the vitreous face is generally self limited, lasting up to one week.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Trypan Blue in the drug label.
# Drug Interactions
There is limited information regarding Trypan Blue Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Teratogenic Effects: Pregnancy Category C. Trypan blue is teratogenic in rats, mice, rabbits, hamsters, dogs, guinea pigs, pigs, and chickens. The majority of teratogenicity studies performed involve intravenous, intraperitoneal, or subcutaneous administration in the rat. The teratogenic dose is 50 mg/kg as a single dose or 25 mg/kg/day during embryogenesis in the rat. These doses are approximately 4,000- and 2,000-fold the maximum recommended human dose of 0.75 mg per injection based in a 60 kg person, assuming that the whole dose is completely absorbed. Characteristic anomalies included neural tube, cardiovascular, vertebral, tail, and eye defects. Trypan blue also caused an increase in post-implantation mortality, and decreased fetal weight. In the monkey, trypan blue caused abortions with single or two daily doses of 50 mg/kg between 20th to 25th days of pregnancy, but no apparent increase in birth defects (approximately 4,000-fold maximum recommended human dose of 0.75 mg per injection, assuming total absorption). There are no adequate and well-controlled studies in pregnant women. Trypan blue should be given to a pregnant woman only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trypan Blue in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trypan Blue during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when trypan blue is administered to a nursing woman.
### Pediatric Use
- The safety and effectiveness of trypan blue have been established in pediatric patients. Use of trypan blue is supported by evidence from an adequate and well-controlled study in pediatric patients.
### Geriatic Use
- No overall differences in safety and effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Trypan Blue with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trypan Blue with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Trypan Blue in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Trypan Blue in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Trypan Blue in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Trypan Blue in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- There is limited information regarding Monitoring of Trypan Blue in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Trypan Blue in the drug label.
# Overdosage
- There is limited information regarding Chronic Overdose of Trypan Blue in the drug label.
# Pharmacology
## Mechanism of Action
- MembraneBlue™ 0.15% selectively stains membranes in the human eye during posterior surgery, such as epiretinal membranes (ERM) and Internal Limiting Membranes (ILM).
## Structure
- MembraneBlue™ 0.15% (trypan blue ophthalmic solution) is a sterile solution of trypan blue (an acid di-azo group dye). MembraneBlue™ 0.15% selectively stains epiretinal membranes during ophthalmic surgical vitrectomy procedures.
- Each mL of MembraneBlue™ 0.15% contains: 1.5 mg trypan blue; 1.9 mg sodium mono-hydrogen orthophosphate (Na2HPO4.2H2O); 0.3 mg sodium di-hydrogen orthophosphate (NaH2PO4.2H2O); 8.2 mg sodium chloride (NaCl); and water for injection. The pH is 7.3 - 7.6. The osmolality is 257-314 mOsm/kg.
- The drug substance trypan blue has the chemical name 3,3’-[(3,3’-dimethyl-4,4’-biphenylylene) bis (azo)] bis(5-amino-4-hydroxy-2,7-naphthalenedisulfonic acid) tetra sodium salt, a molecular weight of 960.8, a molecular formula of C34H24N6Na4O14S4, and has the following chemical structure:
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Trypan Blue in the drug label.
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Trypan Blue in the drug label.
## Nonclinical Toxicology
- Trypan blue is carcinogenic in rats. Wister/Lewis rats developed lymphomas after receiving subcutaneous injections of 1% trypan blue dosed at 50 mg/kg every other week for 52 weeks (total dose approximately 100,000-fold the maximum recommended human dose of 0.75 mg per injection in a 60 kg person, assuming total absorption).
- Trypan blue was mutagenic in the Ames test and caused DNA strand breaks in vitro.
# Clinical Studies
There is limited information regarding Clinical Studies of Trypan Blue in the drug label.
# How Supplied
- MembraneBlue™ 0.15% is supplied as follows:
- 0.5 mL of MembraneBlue™ 0.15% in a sterile single-use Luer Lok, 2.25 mL glass syringe, grey rubber plunger stopper and tip cap with polypropylene plunger rod in a peel pouch. Five pouched products are packed in one distribution box.
## Storage
- MembraneBlue™ 0.15% is stored at 15-25ºC (59-77ºF). Protect from direct sunlight.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Trypan Blue in the drug label.
# Precautions with Alcohol
- Alcohol-Trypan Blue interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MEMBRANEBLUE®[1]
# Look-Alike Drug Names
- A® — B®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Trypan_Blue | |
670b0f77e395eb42f1d444c89b1a0345bd84ae35 | wikidoc | Tumble weed | Tumble weed
# Overview
A tumbleweed is the above-ground part of a plant that, once mature and dry, disengages from the root and tumbles away in the wind. Usually, the tumbleweed is the entire plant apart from the roots, but in a few species it is a flower cluster. The tumbleweed habit is most common in steppe and desert climates. The tumbleweed is a diaspore, aiding in dispersal of propagules (seeds or spores). It does this by scattering the propagules either as it tumbles, or after it has come to rest in a wet location. In the latter case, the tumbleweed opens mechanically as it absorbs water; apart from its propagules, the tumbleweed is dead.
# Plants forming tumbleweeds
Although the number of species with the tumbleweed habit is small, quite a number of these species are common agricultural weeds.
Although thought to be native to Eurasia, several annual species of Salsola (family Amaranthaceae) that form tumbleweeds have become so common in North America that they are a common symbol in Western movies, where they are typically symbolic of desolation in frontier areas. Salsola pestifera became naturalized over large areas of North America after being imported from continental Asia often in shipments with agricultural seeds. Salsola kali is said to have arrived in the United States in shipments of flax seeds to South Dakota in the nineteenth century.
Salsola tragus (Russian thistle) is an annual plant that breaks off at the stem base, forming a tumbleweed that disperses its seeds as it rolls on top of the ground. It seems to have been imported into South Dakota from Russia in 1870 or 1874 in shipments of flaxseed. It has become a noxious weed that has spread throughout North America to inhabit suitable habitats which include areas with disturbed soils like roadsides, cultivated fields and eroded slopes, and in natural habitats that have sparse vegetation like coastal and riparian sands, semi-deserts and deserts. Salsola tragus is the correct name for the narrow-leaved, weedy representative of the S. kali aggregate found widely over North America. It is an extremely variable species with many races which vary in distinctness. Some of these varieties in the past have been divided into subspecies or even separate species. Though it is a noxious weed, Salsola tragus is useful on arid rangelands as forage for livestock.
Other members of the family Amaranthaceae that form tumbleweeds include Amaranthus albus, native to Central America but introduced and weedy in Europe, Asia, and Australia; Amaranthus graecizans naturalized to North America from its native Africa; Amaranthus retroflexus; Corispermum hyssopifolium; Kochia; and Cycloloma atriplicifolium, which is called the plains tumbleweed.
Atriplex rosea called the tumbling oracle or tumbling orach, is a member of the Chenopodiaceae.
In the aster family (Asteraceae), Centaurea diffusa (a knapweed) forms tumbleweeds. This species is native to Eurasia and naturalized in much of North America. Also in this family, Lessingia glandulifera sometimes forms tumbleweeds; it grows in desert areas, chaparral, and open pine forests of the western United States and is usually found on sandy soils.
In the legume family (Fabaceae), species reported to produce tumbleweeds include some members of the genus Psoralea, and Baptisia tinctoria.
In the plantain family (Plantaginaceae), Plantago cretica.
In the Solanaceae, Solanum rostratum.
In the mustard family (Brassicaceae), Sisymbrium altissimum, Crambe maritima, Lepidium, and Anastatica (a resurrection plant) form tumbleweeds. Very similar in habit to Anastatica, but very distantly related, are the spore-bearing Selaginella lepidophylla (a lycopod) and earthstar mushroom family (Geastraceae). All of these curl into a ball when dry, and uncurl when moistened.
A tumbleweed formed from the flower cluster (inflorescence) occurs in some species of the parsley family (Apiaceae).
The garden plant "baby's-breath" (Gypsophila paniculata), which is in the pink family Caryophyllaceae, has a dry inflorescence that forms tumbleweeds. In parts of central and western North America, it has become a common weed in many locations including hayfields and pastures.
# Anatomy
In some species, the tumbleweed is detached from the plant by abscission of the plant stem; abscission has been shown in Psoralea and Kochia.
# Similar diaspores
Diaspores made of inflorescences occur also in some grasses, including Schedonnardus paniculatus and some species of Eragrostis and Aristida. In these plants, the inflorescences break off and tumble in the wind instead of the whole plant. The species of Spinifex from Southeast Asia are prominent examples of this dispersal adaptation. These grasses are often called tumble-grasses, including such species as Panicum capillare and Eragrostis pectinacea in the United States.
In Southern Africa genera of Amaryllidaceae such as Boophane, Crossyne, and to a lesser extent Brunsvigia, bear inflorescences in the form of globular umbels with long, spoke-like pedicels, either effectively at ground level, or breaking off once the stems are dry and the seeds ripe. The light, open, globular structures form very effective tumbleweed diaspores, dropping the seeds usually within a few days as the follicles fail under the wear of rolling. The seeds are fleshy, short-lived, and germinate rapidly where they land. Being poisonous and distasteful, they are not attractive to candidate transport animals, so the rolling diaspore is a very effective strategy for such plants.
Wind dispersed fruits that tumble or roll on the ground, sometimes known as "tumble fruits", are rare. Some are technically achenes. Highly inflated indehiscent fruits that may facilitate tumbling include Alyssopsis, Coluteocarpus, Physoptychis, and Physaria.
# Environmental effects
Tumbleweeds have a significant effect on wind soil erosion in open regions, particularly on dry-land agricultural operations where the outside application of additional moisture is impossible. One study showed that a single Russian Thistle can remove up to 44 gallons of water from the soil while competing with a wheat crop. The amount of water removed from fallow land more subject to erosion would be even higher. In addition to the moisture consumed by the plant, significant damage to the protective soil crust is caused by the tumbleweeds' motion. The damage to the soil surface then provides exposure for subsequent wind damage and topsoil loss.
# Symbolism
The tumbleweed's association with the Western film has led to a highly symbolic meaning in visual media. It has come to represent locations that are desolate, dry, and often humorless, with few or no occupants. A common use is when characters encounter a long abandoned or dismal-looking place: a tumbleweed will be seen rolling past, often accompanied by the sound of a dry, hollow wind. This is sometimes used in locations where tumbleweeds are not expected, for comedic effect (for example in the opening credits of the film Big Lebowski.). Tumbleweeds can also be shown to punctuate a bad joke or a character otherwise making an absurd declaration, with the plant rolling past in the background and the wind effect emphasizing the awkward silence (similar to the sound of crickets). | Tumble weed
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A tumbleweed is the above-ground part of a plant that, once mature and dry, disengages from the root and tumbles away in the wind. Usually, the tumbleweed is the entire plant apart from the roots, but in a few species it is a flower cluster.[1] The tumbleweed habit is most common in steppe and desert climates. The tumbleweed is a diaspore, aiding in dispersal of propagules (seeds or spores). It does this by scattering the propagules either as it tumbles, or after it has come to rest in a wet location.[2] In the latter case, the tumbleweed opens mechanically as it absorbs water; apart from its propagules, the tumbleweed is dead.
# Plants forming tumbleweeds
Although the number of species with the tumbleweed habit is small, quite a number of these species are common agricultural weeds.
Although thought to be native to Eurasia, several annual species of Salsola (family Amaranthaceae) that form tumbleweeds have become so common in North America that they are a common symbol in Western movies, where they are typically symbolic of desolation in frontier areas. Salsola pestifera became naturalized over large areas of North America after being imported from continental Asia often in shipments with agricultural seeds.[3] Salsola kali is said to have arrived in the United States in shipments of flax seeds to South Dakota in the nineteenth century.[4]
Salsola tragus (Russian thistle) is an annual plant that breaks off at the stem base, forming a tumbleweed that disperses its seeds as it rolls on top of the ground. It seems to have been imported into South Dakota from Russia in 1870 or 1874 in shipments of flaxseed. It has become a noxious weed that has spread throughout North America to inhabit suitable habitats which include areas with disturbed soils like roadsides, cultivated fields and eroded slopes, and in natural habitats that have sparse vegetation like coastal and riparian sands, semi-deserts and deserts. Salsola tragus is the correct name for the narrow-leaved, weedy representative of the S. kali aggregate found widely over North America. It is an extremely variable species with many races which vary in distinctness. Some of these varieties in the past have been divided into subspecies or even separate species. Though it is a noxious weed, Salsola tragus is useful on arid rangelands as forage for livestock.[5]
Other members of the family Amaranthaceae that form tumbleweeds include Amaranthus albus, native to Central America but introduced and weedy in Europe, Asia, and Australia; Amaranthus graecizans[6] naturalized to North America from its native Africa;[citation needed] Amaranthus retroflexus; Corispermum hyssopifolium;[7] Kochia; and Cycloloma atriplicifolium, which is called the plains tumbleweed.[8]
Atriplex rosea called the tumbling oracle or tumbling orach, is a member of the Chenopodiaceae.[9][10]
In the aster family (Asteraceae), Centaurea diffusa (a knapweed) forms tumbleweeds. This species is native to Eurasia and naturalized in much of North America. Also in this family, Lessingia glandulifera sometimes forms tumbleweeds; it grows in desert areas, chaparral, and open pine forests of the western United States and is usually found on sandy soils.[11]
In the legume family (Fabaceae), species reported to produce tumbleweeds include some members of the genus Psoralea, and Baptisia tinctoria.
In the plantain family (Plantaginaceae), Plantago cretica.
In the Solanaceae, Solanum rostratum.[7]
In the mustard family (Brassicaceae), Sisymbrium altissimum, Crambe maritima, Lepidium, and Anastatica (a resurrection plant) form tumbleweeds. Very similar in habit to Anastatica, but very distantly related, are the spore-bearing Selaginella lepidophylla (a lycopod) and earthstar mushroom family (Geastraceae). All of these curl into a ball when dry, and uncurl when moistened.
A tumbleweed formed from the flower cluster (inflorescence) occurs in some species of the parsley family (Apiaceae).[1]
The garden plant "baby's-breath" (Gypsophila paniculata), which is in the pink family Caryophyllaceae, has a dry inflorescence that forms tumbleweeds. In parts of central and western North America, it has become a common weed in many locations including hayfields and pastures.[12]
# Anatomy
In some species, the tumbleweed is detached from the plant by abscission of the plant stem; abscission has been shown in Psoralea and Kochia.[13][14]
# Similar diaspores
Diaspores made of inflorescences occur also in some grasses, including Schedonnardus paniculatus and some species of Eragrostis and Aristida.[15] In these plants, the inflorescences break off and tumble in the wind instead of the whole plant. The species of Spinifex from Southeast Asia are prominent examples of this dispersal adaptation.[16] These grasses are often called tumble-grasses, including such species as Panicum capillare and Eragrostis pectinacea in the United States.[17]
In Southern Africa genera of Amaryllidaceae such as Boophane, Crossyne, and to a lesser extent Brunsvigia, bear inflorescences in the form of globular umbels with long, spoke-like pedicels, either effectively at ground level, or breaking off once the stems are dry and the seeds ripe. The light, open, globular structures form very effective tumbleweed diaspores, dropping the seeds usually within a few days as the follicles fail under the wear of rolling. The seeds are fleshy, short-lived, and germinate rapidly where they land. Being poisonous and distasteful, they are not attractive to candidate transport animals, so the rolling diaspore is a very effective strategy for such plants.
Wind dispersed fruits that tumble or roll on the ground, sometimes known as "tumble fruits", are rare. Some are technically achenes. Highly inflated indehiscent fruits that may facilitate tumbling include Alyssopsis,[18] Coluteocarpus,[18] Physoptychis,[18] and Physaria.[18]
# Environmental effects
Tumbleweeds have a significant effect on wind soil erosion in open regions, particularly on dry-land agricultural operations where the outside application of additional moisture is impossible. One study showed that a single Russian Thistle can remove up to 44 gallons of water from the soil while competing with a wheat crop.[19] The amount of water removed from fallow land more subject to erosion would be even higher. In addition to the moisture consumed by the plant, significant damage to the protective soil crust is caused by the tumbleweeds' motion. The damage to the soil surface then provides exposure for subsequent wind damage and topsoil loss.
# Symbolism
The tumbleweed's association with the Western film has led to a highly symbolic meaning in visual media. It has come to represent locations that are desolate, dry, and often humorless, with few or no occupants. A common use is when characters encounter a long abandoned or dismal-looking place: a tumbleweed will be seen rolling past, often accompanied by the sound of a dry, hollow wind. This is sometimes used in locations where tumbleweeds are not expected, for comedic effect (for example in the opening credits of the film Big Lebowski.). Tumbleweeds can also be shown to punctuate a bad joke or a character otherwise making an absurd declaration, with the plant rolling past in the background and the wind effect emphasizing the awkward silence (similar to the sound of crickets). | https://www.wikidoc.org/index.php/Tumble_weed | |
52c9f9da3b3eef06a53c5e3effa2fa355f7e19b9 | wikidoc | Tumor M2-PK | Tumor M2-PK
# Overview
Tumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2 (M2-PK).
Tumor M2-PK is a key enzyme within tumor metabolism and can be used in stool (fecal) samples for the screening of colorectal tumors (= bowel cancer) and in EDTA plasma samples for the follow-up of various cancers.
Tumor M2-PK is not an organ-specific tumor marker, such as PSA. As a biomarker the amount of Tumor M2-PK in stool and EDTA-plasma reflects the specific metabolic status of the tumors.
Sandwich ELISA’s based on two monoclonal antibodies which specifically recognize Tumor M2-PK (the dimeric form of M2-PK) are available for the quantification of Tumor M2-PK in stool and EDTA-plasma samples respectively.
# Tumor M2-PK screening for the early detection of colorectal tumors and polyps
Preliminary clinical studies in Germany, England and Ireland, which tested the detection of fecal Tumor M2-PK as a biomarker for the early detection of colorectal tumors (= bowel cancer), have revealed sensitivities between 73% (in the only published study) and 97 % (in an unpublished conference poster presentation). This means that the test was positive in between 73 and 97 out of every 100 colorectal tumor patients. For polyps with a diameter larger than 1 cm the sensitivity was 60 %; for polyps smaller than 1 cm the sensitivity was about 25 %. The overall sensitivity for all polyps was 40 %.
Most people are more willing to accept non-invasive preventive medical check-ups. Therefore, the measurement of Tumor M2-PK in stool samples, with follow-up by colonoscopy to clarify the Tumor M2-PK positive results, may prove to be an advance in the early detection of colorectal carcinomas. More research is needed before the test can be recommended as a screening procedure.
# Tumor M2-PK measurements in cancer follow-up
Studies from various international working groups have revealed a significantly increased amount of Tumor M2-PK in EDTA-plasma samples of patients with renal, lung, breast, cervical and gastrointestinal tumors (oesophagus, stomach, pancreas, colon, rectum), as well as melanoma (= skin cancer), which correlated with the tumor stage.
The combination of Tumor M2-PK with the appropriate classical tumor marker, such as CEA for bowel cancer, CA 19-9 for pancreatic cancer and CA 72-4 for gastric cancer, significantly increases the sensitivity to detect various cancers.
An important application of the Tumor M2-PK test in EDTA-plasma is for follow-up during tumor therapy, to monitor the success or failure of the chosen treatment, as well as predicting the chances of a “cure” and survival.
If Tumor M2-PK levels decrease during therapy and then remain low after therapy it points towards successful treatment. An increase in the Tumor M2-PK values during or after therapy points towards relapse and/or metastasis.
Increased Tumor M2-PK values can sometimes also occur in severe inflammatory diseases, which must be excluded by differential diagnosis.
# Scientific background to the role of Tumor M2-PK in tumor metabolism
Pyruvate kinase catalyzes the last step within the glycolytic sequence, the dephosphorylation of phosphoenolpyruvate to pyruvate and is responsible for net energy production within the glycolytic pathway.
Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed.
M2-PK is the characteristic isoenzyme of all proliferating cells, such as normal proliferating cells (i.e. fibroblasts, embryonic cells and adult stem cells) and tumor cells.
During tumorigenesis a shift in the isoenzyme equipment of pyruvate kinase always occurs in such a way that the tissue specific isoenzymes, such as L-PK in the liver or M2-PK in the brain, disappear and M2-PK is expressed.
## Role of the tetrameric and dimeric forms of M2-PK within tumor metabolism
M2-PK can occur in two different forms in proliferating cells:
- a tetrameric form, which consists of four subunits
- a dimeric form, consisting of two subunits.
The tetrameric form of M2-PK has a high affinity to its substrate, phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. Furthermore, the tetrameric form of M2-PK is associated with several other glycolytic enzymes within the so-called glycolytic enzyme complex. Due to the close proximity of the enzymes, the association within the glycolytic enzyme complex leads to a highly effective conversion of glucose to lactate.
When M2-PK is mainly in the highly active tetrameric form, which is the case in most normal proliferating cells, glucose is mostly converted to lactate under the production of energy.
The dimeric form of M2-PK is characterized by a low affinity to its substrate phosphoenolpyruvate and is nearly inactive at physiological PEP concentrations.
When M2-PK is mainly in the less active dimeric form, which is the case in tumor cells, all phosphometabolites above pyruvate kinase accumulate and are channelled into synthetic processes which branch off from glycolytic intermediates, such as nucleic acid-, phospholipid-and amino acid synthesis.
Nucleic acids, phospholipids and amino acids are important cell building blocks which are badly needed by highly proliferating cells, such as tumor cells.
Due to the key position of pyruvate kinase within glycolysis, the tetramer : dimer ratio of M2-PK determines whether glucose carbons are converted to pyruvate and lactate under the production of energy (tetrameric form) or channelled into synthetic processes (dimeric form).
In tumor cells M2-PK is mainly in the dimeric form. Therefore, the dimeric form of M2-PK has been termed Tumor M2-PK.
The dimerization of M2-PK in tumor cells is induced by the direct interaction of M2-PK with different oncoproteins.
However, the tetramer : dimer ratio of M2-PK is not constant.
Oxygen starvation or highly accumulated glycolytic intermediates, such as fructose 1,6-bisphosphate (fructose 1,6-P2) or the amino acid serine, induce the reassociation of the dimeric form of M2-PK to the tetrameric form. Consequently, due to the activation of M2-PK, glucose is converted to pyruvate and lactate under the production of energy until the fructose 1,6-P2 levels drop below a certain threshold value, which allows the dissociation of the tetrameric form of M2-PK to the dimeric form. Thereafter, the cycle of oscillation starts again when the fructose 1,6-P2 levels reach a certain upper threshold value which induces the tetramerization of M2-PK.
When M2-PK is mainly in the less active dimeric form, energy is produced by the degradation of the amino acid glutamine to aspartate, pyruvate and lactate, which is termed glutaminolysis.
In tumor cells the increased rate of lactate production in the presence of oxygen is termed the Warburg effect. | Tumor M2-PK
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2 (M2-PK).
Tumor M2-PK is a key enzyme within tumor metabolism and can be used in stool (fecal) samples for the screening of colorectal tumors (= bowel cancer) and in EDTA plasma samples for the follow-up of various cancers.
Tumor M2-PK is not an organ-specific tumor marker, such as PSA. As a biomarker the amount of Tumor M2-PK in stool and EDTA-plasma reflects the specific metabolic status of the tumors.
Sandwich ELISA’s based on two monoclonal antibodies which specifically recognize Tumor M2-PK (the dimeric form of M2-PK) are available for the quantification of Tumor M2-PK in stool and EDTA-plasma samples respectively.
# Tumor M2-PK screening for the early detection of colorectal tumors and polyps
Preliminary clinical studies in Germany, England and Ireland, which tested the detection of fecal Tumor M2-PK as a biomarker for the early detection of colorectal tumors (= bowel cancer), have revealed sensitivities between 73% (in the only published study) and 97 % (in an unpublished conference poster presentation). This means that the test was positive in between 73 and 97 out of every 100 colorectal tumor patients. For polyps with a diameter larger than 1 cm the sensitivity was 60 %; for polyps smaller than 1 cm the sensitivity was about 25 %. The overall sensitivity for all polyps was 40 %.
Most people are more willing to accept non-invasive preventive medical check-ups. Therefore, the measurement of Tumor M2-PK in stool samples, with follow-up by colonoscopy to clarify the Tumor M2-PK positive results, may prove to be an advance in the early detection of colorectal carcinomas. More research is needed before the test can be recommended as a screening procedure.
# Tumor M2-PK measurements in cancer follow-up
Studies from various international working groups have revealed a significantly increased amount of Tumor M2-PK in EDTA-plasma samples of patients with renal, lung, breast, cervical and gastrointestinal tumors (oesophagus, stomach, pancreas, colon, rectum), as well as melanoma (= skin cancer), which correlated with the tumor stage.
The combination of Tumor M2-PK with the appropriate classical tumor marker, such as CEA for bowel cancer, CA 19-9 for pancreatic cancer and CA 72-4 for gastric cancer, significantly increases the sensitivity to detect various cancers.
An important application of the Tumor M2-PK test in EDTA-plasma is for follow-up during tumor therapy, to monitor the success or failure of the chosen treatment, as well as predicting the chances of a “cure” and survival.
If Tumor M2-PK levels decrease during therapy and then remain low after therapy it points towards successful treatment. An increase in the Tumor M2-PK values during or after therapy points towards relapse and/or metastasis.
Increased Tumor M2-PK values can sometimes also occur in severe inflammatory diseases, which must be excluded by differential diagnosis.
# Scientific background to the role of Tumor M2-PK in tumor metabolism
Pyruvate kinase catalyzes the last step within the glycolytic sequence, the dephosphorylation of phosphoenolpyruvate to pyruvate and is responsible for net energy production within the glycolytic pathway.
Depending upon the different metabolic functions of the tissues, different isoenzymes of pyruvate kinase are expressed.
M2-PK is the characteristic isoenzyme of all proliferating cells, such as normal proliferating cells (i.e. fibroblasts, embryonic cells and adult stem cells) and tumor cells.
During tumorigenesis a shift in the isoenzyme equipment of pyruvate kinase always occurs in such a way that the tissue specific isoenzymes, such as L-PK in the liver or M2-PK in the brain, disappear and M2-PK is expressed.
## Role of the tetrameric and dimeric forms of M2-PK within tumor metabolism
M2-PK can occur in two different forms in proliferating cells:
- a tetrameric form, which consists of four subunits
- a dimeric form, consisting of two subunits.
The tetrameric form of M2-PK has a high affinity to its substrate, phosphoenolpyruvate (PEP), and is highly active at physiological PEP concentrations. Furthermore, the tetrameric form of M2-PK is associated with several other glycolytic enzymes within the so-called glycolytic enzyme complex. Due to the close proximity of the enzymes, the association within the glycolytic enzyme complex leads to a highly effective conversion of glucose to lactate.
When M2-PK is mainly in the highly active tetrameric form, which is the case in most normal proliferating cells, glucose is mostly converted to lactate under the production of energy.
The dimeric form of M2-PK is characterized by a low affinity to its substrate phosphoenolpyruvate and is nearly inactive at physiological PEP concentrations.
When M2-PK is mainly in the less active dimeric form, which is the case in tumor cells, all phosphometabolites above pyruvate kinase accumulate and are channelled into synthetic processes which branch off from glycolytic intermediates, such as nucleic acid-, phospholipid-and amino acid synthesis.
Nucleic acids, phospholipids and amino acids are important cell building blocks which are badly needed by highly proliferating cells, such as tumor cells.
Due to the key position of pyruvate kinase within glycolysis, the tetramer : dimer ratio of M2-PK determines whether glucose carbons are converted to pyruvate and lactate under the production of energy (tetrameric form) or channelled into synthetic processes (dimeric form).
In tumor cells M2-PK is mainly in the dimeric form. Therefore, the dimeric form of M2-PK has been termed Tumor M2-PK.
The dimerization of M2-PK in tumor cells is induced by the direct interaction of M2-PK with different oncoproteins.
However, the tetramer : dimer ratio of M2-PK is not constant.
Oxygen starvation or highly accumulated glycolytic intermediates, such as fructose 1,6-bisphosphate (fructose 1,6-P2) or the amino acid serine, induce the reassociation of the dimeric form of M2-PK to the tetrameric form. Consequently, due to the activation of M2-PK, glucose is converted to pyruvate and lactate under the production of energy until the fructose 1,6-P2 levels drop below a certain threshold value, which allows the dissociation of the tetrameric form of M2-PK to the dimeric form. Thereafter, the cycle of oscillation starts again when the fructose 1,6-P2 levels reach a certain upper threshold value which induces the tetramerization of M2-PK.
When M2-PK is mainly in the less active dimeric form, energy is produced by the degradation of the amino acid glutamine to aspartate, pyruvate and lactate, which is termed glutaminolysis.
In tumor cells the increased rate of lactate production in the presence of oxygen is termed the Warburg effect. | https://www.wikidoc.org/index.php/Tumor_M2-PK | |
cb3338091c8909f706a93a875753a18d420076a8 | wikidoc | Turkana Boy | Turkana Boy
Turkana Boy or Nariokotome Boy is the designation given to fossil KNM-WT 15000, a nearly complete skeleton of an 11- or 12-year-old hominid boy who died 1.5 million years ago in the early Pleistocene. The skeleton was discovered in 1984 by Kamoya Kimeu, a member of a team led by Richard Leakey, at Nariokotome near Lake Turkana in Kenya.
# Adolescence and maturity
Turkana Boy is classified as either Homo erectus or Homo ergaster. The shape of the pelvis indicates that it was a male. Based on dental eruption and lack of any epiphyseal union of the skull, anthropologists Tim White and Richard Leakey determined the boy to have been about 12 years old. Other authorities, however, consider that since H. erectus matured faster than modern humans, the boy may have actually been about 9 years old.
Common chimpanzees (Pan troglodytes, for example) mature more quickly than Homo sapiens. Anatomist Raymond Dart discovered the first gracile australopithecine species (Australopithecus africanus) in 1924 in the Taung limestone quarry in South Africa. Tests have shown that A. africanus (Taung child) developed more quickly into adulthood like modern apes.
Turkana Boy appears to have matured at a rate in between modern humans and apes. Other fossils attributable to Homo erectus, Homo heidelbergensis, and Homo neanderthalensis show signs of an increasingly larger birth canal in the female, enabling mothers to give birth to larger brained infants in comparison to modern apes and australopithecines.
# Morphology
The skeleton was about 1.60 m (5 ft 3 in) tall, although he might have been 68 kg (150 lb) and 1.85 m (6 ft 1 in) tall had he lived to adulthood. The total skeleton is made up of 108 bones accounted for. The cranial capacity of Turkana Boy was about 880 cc, although if he had lived to adulthood, it would have been about 910 cc, which is considerably smaller than the 1350 cc cranial capacity of modern humans.
There are several features which seem awkward in comparison to modern humans. The pelvic structure is narrower than in modern Homo sapiens, meaning that Homo ergaster and Homo erectus in both Africa and Asia had a greater ability to run. Their running techniques may have been equivalent to a modern day race track athlete. This hints that the species lived a harsh and demanding lifestyle; most importantly they must have been accomplished hunters rather than scavengers such as Homo habilis. Radical changes are believed to have taken place during the transformation between the australopithecines and Homo species. Because of Homo ergaster's greater height and limb proportions, which are more similar to Homo sapiens than to the ape-like australopithecines, a combination of height and likely absence of fur would have been a necessity.
From 2 million years ago onwards, a cool dark skin would have helped protect these hominins from deadly ultraviolet radiation from the sun. In equatorial Africa, modern humans evolved this trait an estimated 1 million years ago. The loss of thick fur enabled the sweating mechanism to cool the body down to the required 37 °C. The melanin development would have become crucial to surviving in open land. This coloring of the skin is still present in equatorial populations of modern Homo sapiens.
The overall body stature, weight, and proportions coincidentally are somewhat similar to today's ethnic Masai (also known as Maasai) peoples living in modern day Kenya. Tall, dark, slender bodies keep themselves cool by perspiration. However, the similarity should not be taken to be too great. The overall KNM-WT 15000 skeleton still had features (such as a low sloping forehead, strong brow ridges, and the absence of a chin) not seen in present day modern humans. The arms of the species were slightly longer than seen in modern-day humans. It is currently believed that Turkana Boy had a projecting nose rather than the open flat nose-structure seen in apes and possibly acquired in australopithecines. The larger protruding nose helped to keep in moisture at a balanced temperature, cooling the blood in hot arid areas. The opposite could be said for Homo neanderthalensis (Neanderthals), who had unusually large nostrils which would warm and humidify cold and dry air before it reached the throat and lungs.
# Social behavior & language
The fossil skeleton and much other fossil evidence such as Acheulean stone tools prompts the majority of scientists to conclude that Homo ergaster and Homo erectus, unlike their more primitive ancestors, became efficient hunters. The social structure would probably have become more complex with a larger brain volume; the Broca's area of the brain allows speech and is noted by a slight slant on the cranium. Some anthropologists believe that simplistic sounds led to modern language. However, there are contradictory views on the notion of language. It remains controversial when modern human sounds and basic verbs first became used. The various possibilities include:
- 1.9 million years ago (Homo habilis had a large Broca’s area able to be seen in the cranium of KNM ER 1813), possible signs of the earliest ability for speech.
- 1.5 million years ago, on the arrival of several distinct more human-like hominins spread throughout Africa, Europe, and Asia (i.e., Homo erectus).
- 600,000 and 150,000 years ago when archaic Homo sapiens dominated regions in the Pleistocene epoch (several members during this period are considered fully modern Homo sapiens).
- 50,000 years ago (fully modern Homo sapiens had already spread though the Old World and slowly into the New World 20,000 BCE). Some believe language coincided solely with modern humans once culture was established by groups such as Cro-Magnon man in Europe. It is still a matter of debate whether Neanderthals had a modern form of language.
Richard Leakey also mentions in his book Origin of humankind (1995) that Turkana Boy's thoracic vertebrae is narrower than in modern Homo sapiens's, meaning that he could not make complex speech due to less air being received into his lungs. | Turkana Boy
Template:Infobox fossil
Turkana Boy or Nariokotome Boy is the designation given to fossil KNM-WT 15000[1], a nearly complete skeleton of an 11- or 12-year-old hominid boy who died 1.5 million[2] years ago in the early Pleistocene. The skeleton was discovered in 1984 by Kamoya Kimeu, a member of a team led by Richard Leakey, at Nariokotome near Lake Turkana in Kenya.
# Adolescence and maturity
Turkana Boy is classified as either Homo erectus or Homo ergaster. The shape of the pelvis indicates that it was a male. Based on dental eruption and lack of any epiphyseal union of the skull, anthropologists Tim White and Richard Leakey determined the boy to have been about 12 years old. Other authorities, however, consider that since H. erectus matured faster than modern humans, the boy may have actually been about 9 years old.[citation needed]
Common chimpanzees (Pan troglodytes, for example) mature more quickly than Homo sapiens. Anatomist Raymond Dart discovered the first gracile australopithecine species (Australopithecus africanus) in 1924 in the Taung limestone quarry in South Africa. Tests have shown that A. africanus (Taung child) developed more quickly into adulthood like modern apes.
Turkana Boy appears to have matured at a rate in between modern humans and apes. Other fossils attributable to Homo erectus, Homo heidelbergensis, and Homo neanderthalensis show signs of an increasingly larger birth canal in the female, enabling mothers to give birth to larger brained infants in comparison to modern apes and australopithecines.
# Morphology
The skeleton was about 1.60 m (5 ft 3 in) tall, although he might have been 68 kg (150 lb) and 1.85 m (6 ft 1 in) tall had he lived to adulthood. The total skeleton is made up of 108 bones accounted for. The cranial capacity of Turkana Boy was about 880 cc, although if he had lived to adulthood, it would have been about 910 cc, which is considerably smaller than the 1350 cc cranial capacity of modern humans.
There are several features which seem awkward in comparison to modern humans. The pelvic structure is narrower than in modern Homo sapiens, meaning that Homo ergaster and Homo erectus in both Africa and Asia had a greater ability to run. Their running techniques may have been equivalent to a modern day race track athlete. This hints that the species lived a harsh and demanding lifestyle; most importantly they must have been accomplished hunters rather than scavengers such as Homo habilis. Radical changes are believed to have taken place during the transformation between the australopithecines and Homo species. Because of Homo ergaster's greater height and limb proportions, which are more similar to Homo sapiens than to the ape-like australopithecines, a combination of height and likely absence of fur would have been a necessity.
From 2 million years ago onwards, a cool dark skin would have helped protect these hominins from deadly ultraviolet radiation from the sun. In equatorial Africa, modern humans evolved this trait an estimated 1 million years ago. The loss of thick fur enabled the sweating mechanism to cool the body down to the required 37 °C. The melanin development would have become crucial to surviving in open land. This coloring of the skin is still present in equatorial populations of modern Homo sapiens.
The overall body stature, weight, and proportions coincidentally are somewhat similar to today's ethnic Masai (also known as Maasai) peoples living in modern day Kenya. Tall, dark, slender bodies keep themselves cool by perspiration. However, the similarity should not be taken to be too great. The overall KNM-WT 15000 skeleton still had features (such as a low sloping forehead, strong brow ridges, and the absence of a chin) not seen in present day modern humans. The arms of the species were slightly longer than seen in modern-day humans. It is currently believed that Turkana Boy had a projecting nose rather than the open flat nose-structure seen in apes and possibly acquired in australopithecines. The larger protruding nose helped to keep in moisture at a balanced temperature, cooling the blood in hot arid areas. The opposite could be said for Homo neanderthalensis (Neanderthals), who had unusually large nostrils which would warm and humidify cold and dry air before it reached the throat and lungs.
# Social behavior & language
The fossil skeleton and much other fossil evidence such as Acheulean stone tools prompts the majority of scientists to conclude that Homo ergaster and Homo erectus, unlike their more primitive ancestors, became efficient hunters. The social structure would probably have become more complex with a larger brain volume; the Broca's area of the brain allows speech and is noted by a slight slant on the cranium. Some anthropologists believe that simplistic sounds led to modern language. However, there are contradictory views on the notion of language. It remains controversial when modern human sounds and basic verbs first became used. The various possibilities include:
- 1.9 million years ago (Homo habilis had a large Broca’s area able to be seen in the cranium of KNM ER 1813), possible signs of the earliest ability for speech.
- 1.5 million years ago, on the arrival of several distinct more human-like hominins spread throughout Africa, Europe, and Asia (i.e., Homo erectus).
- 600,000 and 150,000 years ago when archaic Homo sapiens dominated regions in the Pleistocene epoch (several members during this period are considered fully modern Homo sapiens).
- 50,000 years ago (fully modern Homo sapiens had already spread though the Old World and slowly into the New World 20,000 BCE). Some believe language coincided solely with modern humans once culture was established by groups such as Cro-Magnon man in Europe. It is still a matter of debate whether Neanderthals had a modern form of language.
Richard Leakey also mentions in his book Origin of humankind (1995) that Turkana Boy's thoracic vertebrae is narrower than in modern Homo sapiens's, meaning that he could not make complex speech due to less air being received into his lungs. | https://www.wikidoc.org/index.php/Turkana_Boy | |
732076692f9d5c9913425cc2ba9b70c46b744730 | wikidoc | Tyrothricin | Tyrothricin
# Overview
Tyrothricin is a cyclic polypeptide-antibiotic mixture from Bacillus brevis. It is a locally effective antibiotic effective against gram-positive bacteria. It is sometimes combined with benzocaine 5 mg to provide relief from sore throats. In systemic intake it can lead to severe side effects, therefore, the use is limited to topical application.
Tyrothricin belongs to the pharmacologically related group of polypeptide antibiotic compounds including colistin, polymyxin B and bacitracin. There is no cross-resistance to these three agents.
# Effect
Tyrothricin inhibits protein biosynthesis of gram-positive organisms, but is completely ineffective against gram-negative.
# Application
The most common use for tyrothricin is inflammation of the throat, gastric mucosa, and angina tonsillaris. In order to use tyrothricin, the mucous membrane must be intact. This is to ensure that tyrothricin will not come into contact with the bloodstream, therefore limiting the risk of systemic absorption.
# Side-effects
Known hypersensitivity reactions are common, temporary loss of balance (see Vestibular system) and nephrotoxic effects, i.e. impairment of renal function. There are no long term studies about its effect on pregnancy and lactation.
# Trade names
Separate preparations: Limexx (AT), Tyrosur (DE)
Compounds: Citropain (CH), Dorithricin (DE, AT), Lemocin (DE, AT, CH), Mebucaine (CH), Mebucasol (CH), Otothricinol (CH), Sangerol (CH), Solmucaine (CH), Trachisan (DE), Tyroqualin (CH) and generic (AT, CH), Tyrozets (UK) | Tyrothricin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Tyrothricin is a cyclic polypeptide-antibiotic mixture from Bacillus brevis.[1] It is a locally effective antibiotic effective against gram-positive bacteria. It is sometimes combined with benzocaine 5 mg to provide relief from sore throats. In systemic intake it can lead to severe side effects, therefore, the use is limited to topical application.
Tyrothricin belongs to the pharmacologically related group of polypeptide antibiotic compounds including colistin, polymyxin B and bacitracin. There is no cross-resistance to these three agents.
# Effect
Tyrothricin inhibits protein biosynthesis of gram-positive organisms, but is completely ineffective against gram-negative.
# Application
The most common use for tyrothricin is inflammation of the throat, gastric mucosa, and angina tonsillaris. In order to use tyrothricin, the mucous membrane must be intact. This is to ensure that tyrothricin will not come into contact with the bloodstream, therefore limiting the risk of systemic absorption.
# Side-effects
Known hypersensitivity reactions are common, temporary loss of balance (see Vestibular system) and nephrotoxic effects, i.e. impairment of renal function. There are no long term studies about its effect on pregnancy and lactation.
# Trade names
Separate preparations: Limexx (AT), Tyrosur (DE)
Compounds: Citropain (CH), Dorithricin (DE, AT), Lemocin (DE, AT, CH), Mebucaine (CH), Mebucasol (CH), Otothricinol (CH), Sangerol (CH), Solmucaine (CH), Trachisan (DE), Tyroqualin (CH) and generic (AT, CH), Tyrozets (UK) | https://www.wikidoc.org/index.php/Tyrothricin | |
7f919bd9de2b4a0efa30b88dc56148341053d337 | wikidoc | Uranium-235 | Uranium-235
Uranium-235 is an isotope of uranium that differs from the element's other common isotope, uranium-238, by its ability to cause a rapidly expanding fission chain reaction, i.e., it is fissile. It is the only fissile isotope found in any economic quantity in nature. It was discovered in 1935 by Arthur Jeffrey Dempster.
If at least one neutron from U-235 fission strikes another nucleus and causes it to fission, then the chain reaction will continue. If the reaction will sustain itself, it is said to be critical, and the mass of U-235 required to produce the critical condition is said to be a critical mass. A critical chain reaction can be achieved at low concentrations of U-235 if the neutrons from fission are moderated to lower their speed, since the probability for fission with slow neutrons is greater. A fission chain reaction produces intermediate mass fragments which are highly radioactive and produce further energy by their radioactive decay. Some of them produce neutrons, called delayed neutrons, which contribute to the fission chain reaction. In nuclear reactors, the reaction is slowed down by the addition of control rods which are made of elements such as boron, cadmium, and hafnium which can absorb a large number of neutrons. In nuclear bombs, the reaction is uncontrolled and the large amount of energy released creates a nuclear explosion.
The fission of one atom of U-235 generates 200 MeV = 3.2 × 10-11 J, i.e. 18 TJ/mol = 77 TJ/kg. However, approximately 5% of this energy is carried away by virtually undetectable neutrinos.
The nuclear cross section for slow thermal neutrons is about 1000 barns. For fast neutrons it is in the order of 1 barn.
Only around 0.72% of all natural uranium is uranium-235, the rest being mostly uranium-238. This concentration is insufficient for a self sustaining reaction in a light water reactor; enrichment, which just means separating out the uranium-238, must take place to get a usable concentration of uranium-235. Pressurised Heavy Water Reactors, other heavy water reactors, and some graphite moderated reactors are known for using unenriched uranium. Uranium which has been processed to boost its uranium-235 proportion is known as enriched uranium, different applications require unique levels of enrichment.
The fissile uranium in nuclear weapons usually contains 85% or more of 235U known as weapon(s)-grade, though for a crude, inefficient weapon 20% is sufficient (called weapon(s)-usable); even less is sufficient, but then the critical mass required rapidly increases. However, judicious use of implosion and neutron reflectors can enable construction of a weapon from a quantity of uranium below the usual critical mass for its level of enrichment, though this would likely only be possible in a country which already had extensive experience in developing nuclear weapons. The Little Boy atomic bomb was fueled by enriched uranium. Most modern nuclear arsenals use plutonium as the fissile component, however U-235 devices remain a nuclear proliferation concern due to the simplicity of this nuclear weapon design.
Uranium-235 has a half-life of 700 million years. | Uranium-235
Template:Infobox isotope
Uranium-235 is an isotope of uranium that differs from the element's other common isotope, uranium-238, by its ability to cause a rapidly expanding fission chain reaction, i.e., it is fissile. It is the only fissile isotope found in any economic quantity in nature. It was discovered in 1935 by Arthur Jeffrey Dempster.
If at least one neutron from U-235 fission strikes another nucleus and causes it to fission, then the chain reaction will continue. If the reaction will sustain itself, it is said to be critical, and the mass of U-235 required to produce the critical condition is said to be a critical mass. A critical chain reaction can be achieved at low concentrations of U-235 if the neutrons from fission are moderated to lower their speed, since the probability for fission with slow neutrons is greater. A fission chain reaction produces intermediate mass fragments which are highly radioactive and produce further energy by their radioactive decay. Some of them produce neutrons, called delayed neutrons, which contribute to the fission chain reaction. In nuclear reactors, the reaction is slowed down by the addition of control rods which are made of elements such as boron, cadmium, and hafnium which can absorb a large number of neutrons. In nuclear bombs, the reaction is uncontrolled and the large amount of energy released creates a nuclear explosion.
The fission of one atom of U-235 generates 200 MeV = 3.2 × 10<sup>-11 J, i.e. 18 TJ/mol = 77 TJ/kg. However, approximately 5% of this energy is carried away by virtually undetectable neutrinos. [1]
The nuclear cross section for slow thermal neutrons is about 1000 barns. For fast neutrons it is in the order of 1 barn. [1]
Only around 0.72% of all natural uranium is uranium-235, the rest being mostly uranium-238. This concentration is insufficient for a self sustaining reaction in a light water reactor; enrichment, which just means separating out the uranium-238, must take place to get a usable concentration of uranium-235. Pressurised Heavy Water Reactors, other heavy water reactors, and some graphite moderated reactors are known for using unenriched uranium. Uranium which has been processed to boost its uranium-235 proportion is known as enriched uranium, different applications require unique levels of enrichment.
The fissile uranium in nuclear weapons usually contains 85% or more of 235U known as weapon(s)-grade, though for a crude, inefficient weapon 20% is sufficient (called weapon(s)-usable); even less is sufficient, but then the critical mass required rapidly increases. However, judicious use of implosion and neutron reflectors can enable construction of a weapon from a quantity of uranium below the usual critical mass for its level of enrichment, though this would likely only be possible in a country which already had extensive experience in developing nuclear weapons. The Little Boy atomic bomb was fueled by enriched uranium. Most modern nuclear arsenals use plutonium as the fissile component[citation needed], however U-235 devices remain a nuclear proliferation concern due to the simplicity of this nuclear weapon design.
Uranium-235 has a half-life of 700 million years.
Template:Isotope | https://www.wikidoc.org/index.php/U-235 | |
25ee0651eb0985b4c9b889cc40ec9de0afa1e1a5 | wikidoc | Ubiquitin C | Ubiquitin C
Polyubiquitin-C is a protein encoded by the UBC gene in humans. Polyubiquitin-C is one of the sources of ubiquitin, along with UBB, UBA52, and RPS27A.
UBC gene is one of the two stress-regulated polyubiquitin genes (UBB and UBC) in mammals. It plays a key role in maintaining cellular ubiquitin levels under stress conditions. Defects of UBC gene could lead to mid-gestation embryonic lethality.
# Structure
## Gene
UBC gene is located at chromosome 12q24.3, consisting of 2 exons. The promoter of the UBC gene contains putative heat shock elements (HSEs), which mediates UBC induction upon stress. UBC gene differs from UBB gene in the number of Ub coding units they contain. Nine to ten Ub units were in the UBC gene.
## Protein
In polyubiquitin-C, the C-terminus of a given ubiquitin molecule is covalently conjugated to either the N-terminal residue or one of seven lysine residues of another ubiquitin molecule. Different linking of ubiquitin chains results in distinct conformations. There are 8 linkage types of polyubiquitin-C, and each type possesses the linkage-dependent dynamics and a linkage-specific conformation.
# Function
The diversity of polyubiquitin-C means that ubiquitylation contributes to the regulation of many cellular events. Polyubiquitin-C doesn’t activate the heat-shock response, but it plays a key role in sustaining the response. UBC gene transcription is induced during stress and provides extra ubiquitin necessary to remove damaged/unfolded proteins. Polyubiquitin-C has important role in diverse biological processes, such as innate immunity, DNA repair and kinase activity. Unanchored polyubiquitin-C are also key signaling molecules that connect and coordinate the proteasome and autophagy to eliminate toxic protein aggregates.
# Clinical significance
Loss of a single UBC allele has no apparent phenotype, while homozygous deletion of UBC gene leads to mid-gestation embryonic lethality due to a defect in fetal liver development, as well as a delay in cell-cycle progression and increased susceptibility to cellular stress. It is also reported that homozygous deletion of UBC gene in mouse embryonic fibroblasts will cause decreased cellular Ub level and reduced viability under oxidative stress.
# Interactions
Polyubiquitin-C has been shown to interact with:
- BIRC2,
- BSG,
- C21orf59,
- CDC2,
- E2F1,
- EGFR,
- HDAC3,
- HIF1A,
- IRAK1,
- KIAA0753.
- MARK4,
- MDM2,
- NDUFA3,
- NFE2L2,
- NOTCH1,
- NUAK1,
- OPRK1,
- P53,
- PCNA
- PARK2,
- RIPK1,
- RPS6KB1,
- S100A10,
- SCNN1A,
- SCNN1G,
- SFPQ,
- SMAD3,
- SMURF2,
- SP1,
- TRAF6, and
- THRA. | Ubiquitin C
Polyubiquitin-C is a protein encoded by the UBC gene in humans.[1][2][3] Polyubiquitin-C is one of the sources of ubiquitin, along with UBB, UBA52, and RPS27A.[4]
UBC gene is one of the two stress-regulated polyubiquitin genes (UBB and UBC) in mammals. It plays a key role in maintaining cellular ubiquitin levels under stress conditions.[5][6] Defects of UBC gene could lead to mid-gestation embryonic lethality.
# Structure
## Gene
UBC gene is located at chromosome 12q24.3, consisting of 2 exons. The promoter of the UBC gene contains putative heat shock elements (HSEs), which mediates UBC induction upon stress. UBC gene differs from UBB gene in the number of Ub coding units they contain.[5] Nine to ten Ub units were in the UBC gene.
## Protein
In polyubiquitin-C, the C-terminus of a given ubiquitin molecule is covalently conjugated to either the N-terminal residue or one of seven lysine residues of another ubiquitin molecule.[7] Different linking of ubiquitin chains results in distinct conformations. There are 8 linkage types of polyubiquitin-C, and each type possesses the linkage-dependent dynamics and a linkage-specific conformation.[8][9]
# Function
The diversity of polyubiquitin-C means that ubiquitylation contributes to the regulation of many cellular events. Polyubiquitin-C doesn’t activate the heat-shock response, but it plays a key role in sustaining the response. UBC gene transcription is induced during stress and provides extra ubiquitin necessary to remove damaged/unfolded proteins.[6][10] Polyubiquitin-C has important role in diverse biological processes, such as innate immunity, DNA repair and kinase activity.[11][12][13] Unanchored polyubiquitin-C are also key signaling molecules that connect and coordinate the proteasome and autophagy to eliminate toxic protein aggregates.[14]
# Clinical significance
Loss of a single UBC allele has no apparent phenotype, while homozygous deletion of UBC gene leads to mid-gestation embryonic lethality due to a defect in fetal liver development, as well as a delay in cell-cycle progression and increased susceptibility to cellular stress.[6] It is also reported that homozygous deletion of UBC gene in mouse embryonic fibroblasts will cause decreased cellular Ub level and reduced viability under oxidative stress.[15]
# Interactions
Polyubiquitin-C has been shown to interact with:
- BIRC2,[16][17][18]
- BSG,[19]
- C21orf59,[20]
- CDC2,[21]
- E2F1,[22]
- EGFR,[23][24][25]
- HDAC3,[21]
- HIF1A,[26][27][28]
- IRAK1,[29][30][31][32]
- KIAA0753.[33]
- MARK4,[34]
- MDM2,[35][36][37]
- NDUFA3,[38]
- NFE2L2,[39][40]
- NOTCH1,[41]
- NUAK1,[34]
- OPRK1,[42]
- P53,[23][35][36][37][43][44][45][46]
- PCNA[47][48][49]
- PARK2,[50][51]
- RIPK1,[16][29][52][53][54]
- RPS6KB1,[55]
- S100A10,[56]
- SCNN1A,[57][58]
- SCNN1G,[57][58]
- SFPQ,[59]
- SMAD3,[60][61]
- SMURF2,[62][63]
- SP1,[64]
- TRAF6,[29][30][52][65][66] and
- THRA.[21] | https://www.wikidoc.org/index.php/UBC_(gene) | |
cc42a20007fa5d7ffe943cf3b8ece5e03f7305c1 | wikidoc | Uhl anomaly | Uhl anomaly
Synonyms and keywords: parchment right ventricle. See also: arrhythmogenic right ventricular dysplasia
# Overview
Uhl anomaly is a very rare congenital heart disease with a partial or total loss of the myocardial muscle in the right ventricle.
# Pathophysiology
There is a total loss of myocardial muscle in the right ventricle. It represents a severe from of arrhythmogenic right ventricular dysplasia.
# Epidemiology and Demographics
Less than 100 cases have been reported between 1900–1993.
# Historical Perspective
Uhl anomaly was first described in 1952.
# Diagnosis
## Fetal echocardiographic findings
Three findings are enlarged right ventricular cavity without apical trabeculation with a thin hypokinetic ventricular wall.
# Sources
- Leon Gerlis, Uhl's anomaly, Orphanet Encyclopedia, January 2003. | Uhl anomaly
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-in-Chief: Keri Shafer, M.D. [2]
Synonyms and keywords: parchment right ventricle. See also: arrhythmogenic right ventricular dysplasia
# Overview
Uhl anomaly is a very rare congenital heart disease with a partial or total loss of the myocardial muscle in the right ventricle.
# Pathophysiology
There is a total loss of myocardial muscle in the right ventricle. It represents a severe from of arrhythmogenic right ventricular dysplasia.
# Epidemiology and Demographics
Less than 100 cases have been reported between 1900–1993.
# Historical Perspective
Uhl anomaly was first described in 1952.[1]
# Diagnosis
## Fetal echocardiographic findings
Three findings are enlarged right ventricular cavity without apical trabeculation with a thin hypokinetic ventricular wall.[2]
# Sources
- Leon Gerlis, Uhl's anomaly, Orphanet Encyclopedia, January 2003. | https://www.wikidoc.org/index.php/Uhl_anomaly | |
3d8b5165149b392b9ebeec140e97c8da07104c5a | wikidoc | Ulmus rubra | Ulmus rubra
The Slippery Elm Ulmus rubra Muhl. is a species of elm native to eastern North America from southeast North Dakota east to southern Quebec and south to northernmost Florida and eastern Texas. Although similar to American Elm in general appearance, it is more closely related to the European Wych Elm, sharing very similar flower structure with that species. It is less susceptible to Dutch elm disease than many elms, and has a different branching pattern. The heartwood is reddish-brown, giving the tree another common name, Red Elm. Other names include Gray Elm, Soft Elm, Moose Elm and Indian Elm.
The Slippery Elm is a deciduous tree reaching 10-20 m tall and 50 cm trunk diameter. The leaves are 10-18 cm long, with a rough texture, coarsely double-serrate margin and an oblique base. The flowers are produced before the leaves in early spring, in clusters of 10-20; the fruit is an oval winged samara 2 cm long containing a single seed in the center. Slippery Elm may be distinguished from American Elm by the hairiness of the buds and twigs (American Elm has smooth buds and twigs), and by the flowers being very short-stalked.
Slippery Elm prefers moisture-rich uplands, but will grow well in dry intermediate soils as well: it is very rare in cultivation beyond the USA.
# Uses
Slippery Elm is a valuable tree which has many different uses. The inner bark can be ground into a nutrient-rich gruel. One can survive on this gruel alone for a relatively short period. It also contains a mucilage that is an excellent remedy for sore throats. It may be dried and ground to a powder, then made into a tea. Either the tea or the gruel may be used to soothe the digestive tract as well, such as with irritable bowel syndrome or gastritis. There are no known contraindications for Slippery Elm, since it consists mainly of mucilage and various nutrients; it is not technically a drug.
The bark has also been used historically as an abortifacient. It was moistened with water and then inserted into the cervix. At one time this was reflected in elm stick laws on the books in several US states that forbid selling pieces of slippery elm bark longer than a certain length. Selling whole Slippery Elm bark is banned in several countries including the UK because of this.
The fibrous inner bark is a strong and durable fibre, which can be spun into thread, twine or rope. It can be used for bow strings, ropes, jewellery, clothing, snowshoe bindings, woven mats, and even some musical instruments.
The wood is used for the hubs of wagon wheels, as it is very shock resistant, owing to the wood's interlocking grain. It is also used for making bows, as it is both strong and flexible.
Once cured, the wood is also excellent for making fire with the bow drill method, as it grinds into a very fine, flammable powder under friction.
# Cultivars
None known.
# Hybrid cultivars
U. rubra enjoyed limited success as a hybrid parent in the 1960s, resulting in the release of Coolshade, Lincoln, Rosehill, and probably Willis. In later years, it was also used in the Wisconsin programme to produce Repura and Revera, although neither of which appear to have been commercially released (2007).
# Arboreta etc. accessions
- Arnold Arboretum, acc. nos. 737-88, 738-88, both of unrecorded provenance.
- Brenton Arboretum, Dallas Center, Iowa. No details available.
- Longwood Gardens, acc. no. L-3002, of unrecorded provenance.
- Smith College, acc. no. 8119PA.
- Brighton & Hove City Council,NCCPG elm collection .
- Hortus Botanicus Nationalis, Salaspils, Latvia acc. nos. 18168, 18169, 18170.
- Royal Botanic Garden Wakehurst Place, acc. no. 1973-21050.
- Thenford House arboretum, Northamptonshire, UK, no details available.
- University of Copenhagen Botanic Garden (no details available)
# Nurseries
- Arborvillage, Holt, Missouri.
- Grange Farm Plants, Spalding, Lincs., UK.
- Salley Gardens, UK.
- Arne Herbs, UK.
# Seed suppliers
- B and T World Seeds, Paguignan, 34210 Aigues-Vives, France
# Gallery
- Mature bark
Mature bark
- Leaf
Leaf | Ulmus rubra
The Slippery Elm Ulmus rubra Muhl. is a species of elm native to eastern North America from southeast North Dakota east to southern Quebec and south to northernmost Florida and eastern Texas. Although similar to American Elm in general appearance, it is more closely related to the European Wych Elm, sharing very similar flower structure with that species. It is less susceptible to Dutch elm disease than many elms, and has a different branching pattern. The heartwood is reddish-brown, giving the tree another common name, Red Elm. Other names include Gray Elm, Soft Elm, Moose Elm and Indian Elm.
The Slippery Elm is a deciduous tree reaching 10-20 m tall and 50 cm trunk diameter. The leaves are 10-18 cm long, with a rough texture, coarsely double-serrate margin and an oblique base. The flowers are produced before the leaves in early spring, in clusters of 10-20; the fruit is an oval winged samara 2 cm long containing a single seed in the center. Slippery Elm may be distinguished from American Elm by the hairiness of the buds and twigs (American Elm has smooth buds and twigs), and by the flowers being very short-stalked.
Slippery Elm prefers moisture-rich uplands, but will grow well in dry intermediate soils as well: it is very rare in cultivation beyond the USA.
# Uses
Slippery Elm is a valuable tree which has many different uses. The inner bark can be ground into a nutrient-rich gruel. One can survive on this gruel alone for a relatively short period. It also contains a mucilage that is an excellent remedy for sore throats. It may be dried and ground to a powder, then made into a tea. Either the tea or the gruel may be used to soothe the digestive tract as well, such as with irritable bowel syndrome or gastritis. There are no known contraindications for Slippery Elm, since it consists mainly of mucilage and various nutrients; it is not technically a drug. [1]
The bark has also been used historically as an abortifacient. It was moistened with water and then inserted into the cervix. At one time this was reflected in elm stick laws on the books in several US states that forbid selling pieces of slippery elm bark longer than a certain length. Selling whole Slippery Elm bark is banned in several countries including the UK because of this.
The fibrous inner bark is a strong and durable fibre, which can be spun into thread, twine or rope. It can be used for bow strings, ropes, jewellery, clothing, snowshoe bindings, woven mats, and even some musical instruments.
The wood is used for the hubs of wagon wheels, as it is very shock resistant, owing to the wood's interlocking grain. It is also used for making bows, as it is both strong and flexible.
Once cured, the wood is also excellent for making fire with the bow drill method, as it grinds into a very fine, flammable powder under friction.
# Cultivars
None known.
# Hybrid cultivars
U. rubra enjoyed limited success as a hybrid parent in the 1960s, resulting in the release of Coolshade, Lincoln, Rosehill, and probably Willis. In later years, it was also used in the Wisconsin programme to produce Repura and Revera, although neither of which appear to have been commercially released (2007).
# Arboreta etc. accessions
- Arnold Arboretum, acc. nos. 737-88, 738-88, both of unrecorded provenance.
- Brenton Arboretum, Dallas Center, Iowa. No details available.
- Longwood Gardens, acc. no. L-3002, of unrecorded provenance.
- Smith College, acc. no. 8119PA.
- Brighton & Hove City Council,NCCPG elm collection [1].
- Hortus Botanicus Nationalis, Salaspils, Latvia acc. nos. 18168, 18169, 18170.
- Royal Botanic Garden Wakehurst Place, acc. no. 1973-21050.
- Thenford House arboretum, Northamptonshire, UK, no details available.
- University of Copenhagen Botanic Garden (no details available)
# Nurseries
- Arborvillage, Holt, Missouri.
- Grange Farm Plants, Spalding, Lincs., UK.
- Salley Gardens, UK.
- Arne Herbs, UK.
# Seed suppliers
- B and T World Seeds, Paguignan, 34210 Aigues-Vives, France
# Gallery
- Mature bark
Mature bark
- Leaf
Leaf | https://www.wikidoc.org/index.php/Ulmus_rubra | |
a692b2e1b6570dd9264f9c18671dd2b2614b1670 | wikidoc | Ulnar nerve | Ulnar nerve
In human anatomy, the ulnar nerve is a nerve which runs from the shoulder to the hand, at one part running near the ulna bone. It is the only exposed nerve in the human body (it is unprotected for a few centimeters at the elbow). When someone says "hitting their funny bone" it is the aggravation of this nerve that is being referred to.
# Course
The ulnar nerve comes from the medial cord of the brachial plexus, and runs inferior on the medial/posterior aspect of the humerus down the arm, going behind the medial epicondyle at the elbow. Because of the mild pain and tingling throughout the forearm associated with an inadvertent impact of the nerve at this point, it is usually called the funny bone. (It may also have to do with its location relative to the humerus, as the name "humerus" is a homonym to the word "humorous").
It enters the anterior (front) side of the forearm and runs alongside the ulna. There it supplies one and a half muscles (flexor carpi ulnaris & medial half of flexor digiti profundus). It soon joins with the ulnar artery, and the two travel inferiorly together, deep to the flexor carpi ulnaris muscle.
After its journey down the ulna, the ulnar nerve enters the palm of the hand. Unlike the median nerve which travels below the flexor retinaculum of the hand and through the carpal tunnel, the ulnar nerve and artery pass superficial to the flexor retinaculum via the ulnar canal.
# Branches and innervation
## Muscular
The ulnar nerve and its branches innervate the following muscles in the forearm and hand:
An Articular branch that passes to the elbow joint while the ulnar nerve is passing between the olecranon and medial epicondyle of the femur.
- In the forearm, via the muscular branches of ulnar nerve:
Flexor carpi ulnaris
Flexor digitorum profundus (medial half)
- Flexor carpi ulnaris
- Flexor digitorum profundus (medial half)
- In the hand, via the deep branch of ulnar nerve:
hypothenar muscles
Opponens digiti minimi
Abductor digiti minimi
Flexor digiti minimi brevis
Adductor pollicis
The third and fourth lumbrical muscles
Dorsal interossei
Palmar interossei
- hypothenar muscles
Opponens digiti minimi
Abductor digiti minimi
Flexor digiti minimi brevis
- Opponens digiti minimi
- Abductor digiti minimi
- Flexor digiti minimi brevis
- Adductor pollicis
- The third and fourth lumbrical muscles
- Dorsal interossei
- Palmar interossei
- In the hand, via the superficial branch of ulnar nerve:
Palmaris brevis
- Palmaris brevis
## Cutaneous
The ulnar nerve also provides sensory innervation to the part of the hand corresponding to the fourth and fifth digits:
- Palmar branch of ulnar nerve - anterior
- Dorsal branch of ulnar nerve - posterior
# Ulnar nerve entrapment
The Ulnar nerve can be trapped or pinched in various ways as it proceeds down the arm from the Brachial plexus to the ring and middle fingers. One common cause is cubital tunnel syndrome, where the tunnel runs the inner outside side of the elbow. Pinching of the nerve often causes tingling symptoms in the little and ring fingers. In some cases moderate to severe pain is experienced from pinching this nerve. Often such pins and needles sensations can be caused by sleeping wrongly on your arm, but sometimes the problems last for days. In severe cases, surgery is performed. | Ulnar nerve
Template:Infobox Nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In human anatomy, the ulnar nerve is a nerve which runs from the shoulder to the hand, at one part running near the ulna bone. It is the only exposed nerve in the human body (it is unprotected for a few centimeters at the elbow). When someone says "hitting their funny bone" it is the aggravation of this nerve that is being referred to.
# Course
The ulnar nerve comes from the medial cord of the brachial plexus, and runs inferior on the medial/posterior aspect of the humerus down the arm, going behind the medial epicondyle at the elbow. Because of the mild pain and tingling throughout the forearm associated with an inadvertent impact of the nerve at this point, it is usually called the funny bone. (It may also have to do with its location relative to the humerus, as the name "humerus" is a homonym to the word "humorous").
It enters the anterior (front) side of the forearm and runs alongside the ulna. There it supplies one and a half muscles (flexor carpi ulnaris & medial half of flexor digiti profundus). It soon joins with the ulnar artery, and the two travel inferiorly together, deep to the flexor carpi ulnaris muscle.
After its journey down the ulna, the ulnar nerve enters the palm of the hand. Unlike the median nerve which travels below the flexor retinaculum of the hand and through the carpal tunnel, the ulnar nerve and artery pass superficial to the flexor retinaculum via the ulnar canal.
# Branches and innervation
## Muscular
The ulnar nerve and its branches innervate the following muscles in the forearm and hand:
An Articular branch that passes to the elbow joint while the ulnar nerve is passing between the olecranon and medial epicondyle of the femur.
- In the forearm, via the muscular branches of ulnar nerve:
Flexor carpi ulnaris
Flexor digitorum profundus (medial half)
- Flexor carpi ulnaris
- Flexor digitorum profundus (medial half)
- In the hand, via the deep branch of ulnar nerve:
hypothenar muscles
Opponens digiti minimi
Abductor digiti minimi
Flexor digiti minimi brevis
Adductor pollicis
The third and fourth lumbrical muscles
Dorsal interossei
Palmar interossei
- hypothenar muscles
Opponens digiti minimi
Abductor digiti minimi
Flexor digiti minimi brevis
- Opponens digiti minimi
- Abductor digiti minimi
- Flexor digiti minimi brevis
- Adductor pollicis
- The third and fourth lumbrical muscles
- Dorsal interossei
- Palmar interossei
- In the hand, via the superficial branch of ulnar nerve:
Palmaris brevis
- Palmaris brevis
## Cutaneous
The ulnar nerve also provides sensory innervation to the part of the hand corresponding to the fourth and fifth digits:
- Palmar branch of ulnar nerve - anterior
- Dorsal branch of ulnar nerve - posterior
# Ulnar nerve entrapment
The Ulnar nerve can be trapped or pinched in various ways as it proceeds down the arm from the Brachial plexus to the ring and middle fingers. One common cause is cubital tunnel syndrome, where the tunnel runs the inner outside side of the elbow. Pinching of the nerve often causes tingling symptoms in the little and ring fingers. In some cases moderate to severe pain is experienced from pinching this nerve. Often such pins and needles sensations can be caused by sleeping wrongly on your arm, but sometimes the problems last for days. In severe cases, surgery is performed. | https://www.wikidoc.org/index.php/Ulnar_nerve | |
2926605ccc3ce0f0ad3cda688c78831012bc9b3c | wikidoc | Uncertainty | Uncertainty
Uncertainty is a term used in subtly different ways in a number of fields, including philosophy, statistics, economics, finance, insurance, psychology, sociology, engineering, and information science. It applies to predictions of future events, to physical measurements already made, or to the unknown.
# Concepts
In his seminal work Risk, Uncertainty, and Profit University of Chicago economist Frank Knight (1921) established the important distinction between risk and uncertainty:
Although the terms are used in various ways among the general public, many specialists in decision theory, statistics and other quantitative fields have defined uncertainty and risk more specifically. Doug Hubbard defines uncertainty and risk as:
- Uncertainty: The lack of certainty, A state of having limited knowledge where it is impossible to exactly describe existing state or future outcome, more than one possible outcome.
- Measurement of Uncertainty:A set of possible states or outcomes where probabilities are assigned to each possible state or outcome - this also includes the application of a probability density function to continuous variables
- Risk:A state of uncertainty where some possible outcomes have an undesired effect or significant loss.
- Measurement of Risk:A set of measured uncertainties where some possible outcomes are losses, and the magnitudes of those losses - this also includes loss functions over continuous variables.
There are other different taxonomy of uncertainties and decisions that include a more broad sense of uncertainty and how it should be approached from an ethics perspective :
For example, if you do not know whether it will rain tomorrow, then you have a state of uncertainty. If you apply probabilities to the possible outcomes using weather forecasts or even just a calibrated probability assessment, you have quantified the uncertainty. Suppose you quantify your uncertainty as a 90% chance of sunshine. If you are planning a major, costly, outdoor event for tomorrow then you have risk since there is a 10% chance of rain and rain would be undesirable. Furthermore, if this is a business event and you would lose $100,000 if it rains, then you have quantified the risk (a 10% chance of losing $100,000). These situation can be made even more realistic by quantifying light rain vs. heavy rain, the cost of delays vs. outright cancellation, etc.
Some may represent the risk in this example as the "expected opportunity loss" (EOL) or the chance of the loss multiplied by the amount of the loss (10% x $100,000 = $10,000). That is useful if the organizer of the event is "risk neutral" which most people are not. Most would be willing to pay a premium to avoid the loss. An insurance company, for example, would compute an EOL as a minimum for any insurance coverage, then add on to that other operating costs and profit. Since many people are willing to buy insurance for many reasons, then clearly the EOL alone is not the perceived value of avoiding the risk.
Quantitative uses of the terms uncertainty and risk are fairly consistent from fields such as probability theory, actuarial science, and information theory. Some also create new terms without substantially changing the definitions of uncertainty or risk. For example, surprisal is a variation on uncertainty sometimes uses in information theory. But outside of the more mathematical uses of the term, usage may vary widely. In cognitive psychology, uncertainty can be real, or just a matter of perception, such as expectations, threats, etc.
Vagueness or ambiguity are sometimes described as "second order uncertainty", where there is uncertainty even about the definitions of uncertain states or outcomes. The difference here is that this uncertainty is about the human definitions and concepts not an objective fact of nature. It has been argued that ambiguity, however, is always avoidable while uncertainty (of the "first order" kind) is not necessarily avoidable.:
Uncertainty may be purely a consequence of a lack of knowledge of obtainable facts. That is, you may be uncertain about whether a new rocket design will work, but this uncertainty can be removed with further analysis and experimentation. At the subatomic level, however, uncertainty may be a fundamental and unavoidable property of the universe. In quantum mechanics, the Heisenberg Uncertainty Principle puts limits on how much an observer can ever know about the position and velocity of a particle. This may not just be ignorance of potentially obtainable facts but that there is no fact to be found. There is some controversy in physics as to whether such uncertainty is an irreducible property of nature or if there are "hidden variables" that would describe the state of a particle even more exactly than Heisenberg's uncertainty principle allows.
# Measures
The uncertainty of a measurement is stated by giving a range of values which are likely to enclose the true value. This may be denoted by error bars on a graph, or as value ± uncertainty, or as decimal fraction(uncertainty). The latter "concise notation" is used for example by IUPAC in stating the atomic mass of elements. There, 1.00794(7) stands for 1.00794 ± 0.00007.
Often, the uncertainty of a measurement is found by repeating the measurement enough times to get a good estimate of the standard deviation of the values. Then, any single value has an uncertainty equal to the standard deviation. However, if the values are averaged, then the mean measurement value has a much smaller uncertainty, equal to the standard error of the mean, which is the standard deviation divided by the square root of the number of measurements.
When the uncertainty represents the standard error of the measurement, then about 68.2% of the time, the true value of the measured quantity falls within the stated uncertainty range. For example, it is likely that for 31.8% of the atomic mass values given on the list of elements by atomic mass, the true value lies outside of the stated range. If the width of the interval is doubled, then probably only 4.6% of the true values lie outside the doubled interval, and if the width is tripled, probably only 0.3% lie outside. These values follow from the properties of the normal distribution, and they apply only if the measurement process produces normally distributed errors. In that case, the quoted standard errors are easily converted to 68.2% ("one sigma"), 95.4% ("two sigma"), or 99.7% ("three sigma") confidence intervals.
# Applications
- Investing in financial markets such as the stock market.
- Uncertainty is used in engineering notation when talking about significant figures. Or the possible error involved in measuring things such as distance.
- Uncertainty is designed into games, most notably in gambling, where chance is central to play.
- In scientific modelling, in which the prediction of future events should be understood to have a range of expected values.
- In physics in certain situations, uncertainty has been elevated into a principle, the uncertainty principle.
- In weather forecasting it is now commonplace to include data on the degree of uncertainty in a weather forecast.
- Uncertainty is often an important factor in economics. According to economist Frank Knight, it is different from risk, where there is a specific probability assigned to each outcome (as when flipping a fair coin). Uncertainty involves a situation that has unknown probabilities, while the estimated probabilities of possible outcomes need not add to unity.
- In risk assessment and risk management.
- In metrology, measurement uncertainty is a central concept quantifying the dispersion one may reasonably attribute to a measurement result. Such an uncertainty can also be referred to as a measurement error. In daily life, measurement uncertainty is often implicit ("He is 6 feet tall" give or take a few inches), while for any serious use an explicit statement of the measurement uncertainty is necessary. The expected measurement uncertainty of many measuring instruments (scales, oscilloscopes, force gages, rulers, thermometers, etc) is often stated in the manufacturers specification.
- Type A, those which are evaluated by statistical methods,
- Type B, those which are evaluated by other means, e.g. by assigning a probability distribution.
- Uncertainty has been a common theme in art, both as a thematic device (see, for example, the indecision of Hamlet), and as a quandary for the artist (such as Martin Creed's difficulty with deciding what artworks to make). | Uncertainty
Template:Certainty
Uncertainty is a term used in subtly different ways in a number of fields, including philosophy, statistics, economics, finance, insurance, psychology, sociology, engineering, and information science. It applies to predictions of future events, to physical measurements already made, or to the unknown.
# Concepts
In his seminal work Risk, Uncertainty, and Profit[1] University of Chicago economist Frank Knight (1921) established the important distinction between risk and uncertainty:
Although the terms are used in various ways among the general public, many specialists in decision theory, statistics and other quantitative fields have defined uncertainty and risk more specifically. Doug Hubbard defines uncertainty and risk as:[2]
- Uncertainty: The lack of certainty, A state of having limited knowledge where it is impossible to exactly describe existing state or future outcome, more than one possible outcome.
- Measurement of Uncertainty:A set of possible states or outcomes where probabilities are assigned to each possible state or outcome - this also includes the application of a probability density function to continuous variables
- Risk:A state of uncertainty where some possible outcomes have an undesired effect or significant loss.
- Measurement of Risk:A set of measured uncertainties where some possible outcomes are losses, and the magnitudes of those losses - this also includes loss functions over continuous variables.
There are other different taxonomy of uncertainties and decisions that include a more broad sense of uncertainty and how it should be approached from an ethics perspective [3]:
For example, if you do not know whether it will rain tomorrow, then you have a state of uncertainty. If you apply probabilities to the possible outcomes using weather forecasts or even just a calibrated probability assessment, you have quantified the uncertainty. Suppose you quantify your uncertainty as a 90% chance of sunshine. If you are planning a major, costly, outdoor event for tomorrow then you have risk since there is a 10% chance of rain and rain would be undesirable. Furthermore, if this is a business event and you would lose $100,000 if it rains, then you have quantified the risk (a 10% chance of losing $100,000). These situation can be made even more realistic by quantifying light rain vs. heavy rain, the cost of delays vs. outright cancellation, etc.
Some may represent the risk in this example as the "expected opportunity loss" (EOL) or the chance of the loss multiplied by the amount of the loss (10% x $100,000 = $10,000). That is useful if the organizer of the event is "risk neutral" which most people are not. Most would be willing to pay a premium to avoid the loss. An insurance company, for example, would compute an EOL as a minimum for any insurance coverage, then add on to that other operating costs and profit. Since many people are willing to buy insurance for many reasons, then clearly the EOL alone is not the perceived value of avoiding the risk.
Quantitative uses of the terms uncertainty and risk are fairly consistent from fields such as probability theory, actuarial science, and information theory. Some also create new terms without substantially changing the definitions of uncertainty or risk. For example, surprisal is a variation on uncertainty sometimes uses in information theory. But outside of the more mathematical uses of the term, usage may vary widely. In cognitive psychology, uncertainty can be real, or just a matter of perception, such as expectations, threats, etc.
Vagueness or ambiguity are sometimes described as "second order uncertainty", where there is uncertainty even about the definitions of uncertain states or outcomes. The difference here is that this uncertainty is about the human definitions and concepts not an objective fact of nature. It has been argued that ambiguity, however, is always avoidable while uncertainty (of the "first order" kind) is not necessarily avoidable.[4]:
Uncertainty may be purely a consequence of a lack of knowledge of obtainable facts. That is, you may be uncertain about whether a new rocket design will work, but this uncertainty can be removed with further analysis and experimentation. At the subatomic level, however, uncertainty may be a fundamental and unavoidable property of the universe. In quantum mechanics, the Heisenberg Uncertainty Principle puts limits on how much an observer can ever know about the position and velocity of a particle. This may not just be ignorance of potentially obtainable facts but that there is no fact to be found. There is some controversy in physics as to whether such uncertainty is an irreducible property of nature or if there are "hidden variables" that would describe the state of a particle even more exactly than Heisenberg's uncertainty principle allows.
# Measures
The uncertainty of a measurement is stated by giving a range of values which are likely to enclose the true value. This may be denoted by error bars on a graph, or as value ± uncertainty, or as decimal fraction(uncertainty). The latter "concise notation" is used for example by IUPAC in stating the atomic mass of elements. There, 1.00794(7) stands for 1.00794 ± 0.00007.
Often, the uncertainty of a measurement is found by repeating the measurement enough times to get a good estimate of the standard deviation of the values. Then, any single value has an uncertainty equal to the standard deviation. However, if the values are averaged, then the mean measurement value has a much smaller uncertainty, equal to the standard error of the mean, which is the standard deviation divided by the square root of the number of measurements.
When the uncertainty represents the standard error of the measurement, then about 68.2% of the time, the true value of the measured quantity falls within the stated uncertainty range. For example, it is likely that for 31.8% of the atomic mass values given on the list of elements by atomic mass, the true value lies outside of the stated range. If the width of the interval is doubled, then probably only 4.6% of the true values lie outside the doubled interval, and if the width is tripled, probably only 0.3% lie outside. These values follow from the properties of the normal distribution, and they apply only if the measurement process produces normally distributed errors. In that case, the quoted standard errors are easily converted to 68.2% ("one sigma"), 95.4% ("two sigma"), or 99.7% ("three sigma") confidence intervals.
# Applications
- Investing in financial markets such as the stock market.
- Uncertainty is used in engineering notation when talking about significant figures. Or the possible error involved in measuring things such as distance.
- Uncertainty is designed into games, most notably in gambling, where chance is central to play.
- In scientific modelling, in which the prediction of future events should be understood to have a range of expected values.
- In physics in certain situations, uncertainty has been elevated into a principle, the uncertainty principle.
- In weather forecasting it is now commonplace to include data on the degree of uncertainty in a weather forecast.
- Uncertainty is often an important factor in economics. According to economist Frank Knight, it is different from risk, where there is a specific probability assigned to each outcome (as when flipping a fair coin). Uncertainty involves a situation that has unknown probabilities, while the estimated probabilities of possible outcomes need not add to unity.
- In risk assessment and risk management.[5]
- In metrology, measurement uncertainty is a central concept quantifying the dispersion one may reasonably attribute to a measurement result. Such an uncertainty can also be referred to as a measurement error. In daily life, measurement uncertainty is often implicit ("He is 6 feet tall" give or take a few inches), while for any serious use an explicit statement of the measurement uncertainty is necessary. The expected measurement uncertainty of many measuring instruments (scales, oscilloscopes, force gages, rulers, thermometers, etc) is often stated in the manufacturers specification.
- Type A, those which are evaluated by statistical methods,
- Type B, those which are evaluated by other means, e.g. by assigning a probability distribution.
- Uncertainty has been a common theme in art, both as a thematic device (see, for example, the indecision of Hamlet), and as a quandary for the artist (such as Martin Creed's difficulty with deciding what artworks to make). | https://www.wikidoc.org/index.php/Uncertainty | |
8331bc12a96e7c0cd0d0f0a2076a7afd3e5d52a0 | wikidoc | Underweight | Underweight
The term underweight refers to a human who is considered to be under a healthy weight. The definition is usually made with reference to the body mass index (BMI). A BMI of under 18.5 is usually referred to as underweight. It is important to note that the BMI is a statistical estimate and some individuals classified as underweight may be perfectly healthy. In fact, caloric restriction may be a viable means of increasing the lifespan, and it can easily lead to a BMI of less than 18.5. This medical definition of underweight may differ from other uses of the term, such as those based on attractiveness.
# Causes
The most common cause of a person being underweight is primarily malnutrition caused by the unavailability of adequate food, which can run as high as 50% in parts of sub-Saharan Africa and south Asia. The effects of primary malnutrition may be amplified by disease; even easily treatable diseases such as diarrhea may lead to death.
In the presence of adequate food resources, underweight is generally the result of mental or physical disease. There are hundreds of possible medical causes for excessive weight loss or a person being underweight. Some of the more prevalent include:
- Poverty
- Famine
- Torture
- Anorexia Nervosa
- Bulimia Nervosa
- Cancer Treatment
- Tuberculosis
- Hyperthyroidism
- Type 1 Diabetes
- Anxiety and depressive disorders
- Drug abuse
- Inflammatory bowel disease
- Malfunctioning digestive organs
- Dental pain
- Obsessive over-training
- HIV/AIDS
- Genetics
- Stimulant use
# Problems
The most immediate problem with underweight is that it might be secondary to, and/or symptomatic of, an underlying disease. Unexplained weight loss requires professional medical diagnosis.
Underweight can also be a primary causative condition. Severely underweight individuals may have poor physical stamina and a weak immune system, leaving them open to infection. According to Robert E. Black of the Johns Hopkins School of Public Health, "Underweight status ... and micronutrient deficiencies also cause decreases in immune and non-immune host defenses, and should be classified as underlying causes of death if followed by infectious diseases that are the terminal associated causes."
People who are malnutrative underweight raise special concerns, as not only gross caloric intake may be inadequate, but also intake and absorption of other vital nutrients, especially essential amino acids and micronutrients such as vitamins and minerals.
In women, being grossly underweight can result in amenorrhea (absence of menstruation) and possible complications during pregnancy. It can also cause anemia and hair loss.
Underweight is an established risk factor for osteoporosis even for young people. This is a particular insidious consequence, because the affected persons do not notice the danger, they can feel fit and may be brilliant for example in endurance sports. After the occurrence of first spontaneous fractures the damage is often already irreversible.
# Weight gain
If an individual is severely underweight to the point where problems with his or her health develop, it may be necessary for the person to make a concentrated effort to gain weight. The treatment for an underweight individual is to increase the food energy intake so that more food energy is consumed than is being used as work. It is usually suggested that weight training is also to be undertaken to increase muscle mass.
If weight loss results from a disease, resolving the illness and consuming adequate calories can bring many underweight individuals to a healthy body weight. | Underweight
The term underweight refers to a human who is considered to be under a healthy weight. The definition is usually made with reference to the body mass index (BMI). A BMI of under 18.5 is usually referred to as underweight[1]. It is important to note that the BMI is a statistical estimate and some individuals classified as underweight may be perfectly healthy. In fact, caloric restriction may be a viable means of increasing the lifespan, and it can easily lead to a BMI of less than 18.5. This medical definition of underweight may differ from other uses of the term, such as those based on attractiveness.
# Causes
The most common cause of a person being underweight is primarily malnutrition caused by the unavailability of adequate food, which can run as high as 50% in parts of sub-Saharan Africa and south Asia. The effects of primary malnutrition may be amplified by disease; even easily treatable diseases such as diarrhea may lead to death.
In the presence of adequate food resources, underweight is generally the result of mental or physical disease. There are hundreds of possible medical causes for excessive weight loss or a person being underweight. Some of the more prevalent include:
- Poverty
- Famine
- Torture
- Anorexia Nervosa
- Bulimia Nervosa
- Cancer Treatment
- Tuberculosis
- Hyperthyroidism
- Type 1 Diabetes
- Anxiety and depressive disorders
- Drug abuse
- Inflammatory bowel disease
- Malfunctioning digestive organs
- Dental pain
- Obsessive over-training
- HIV/AIDS
- Genetics
- Stimulant use
# Problems
The most immediate problem with underweight is that it might be secondary to, and/or symptomatic of, an underlying disease. Unexplained weight loss requires professional medical diagnosis.
Underweight can also be a primary causative condition. Severely underweight individuals may have poor physical stamina and a weak immune system, leaving them open to infection. According to Robert E. Black of the Johns Hopkins School of Public Health, "Underweight status ... and micronutrient deficiencies also cause decreases in immune and non-immune host defenses, and should be classified as underlying causes of death if followed by infectious diseases that are the terminal associated causes."[2]
People who are malnutrative underweight raise special concerns, as not only gross caloric intake may be inadequate, but also intake and absorption of other vital nutrients, especially essential amino acids and micronutrients such as vitamins and minerals.
In women, being grossly underweight can result in amenorrhea[3] (absence of menstruation) and possible complications during pregnancy. It can also cause anemia and hair loss.
Underweight is an established risk factor for osteoporosis[4] even for young people. This is a particular insidious consequence, because the affected persons do not notice the danger, they can feel fit and may be brilliant for example in endurance sports. After the occurrence of first spontaneous fractures the damage is often already irreversible.
# Weight gain
If an individual is severely underweight to the point where problems with his or her health develop, it may be necessary for the person to make a concentrated effort to gain weight. The treatment for an underweight individual is to increase the food energy intake so that more food energy is consumed than is being used as work. It is usually suggested that weight training is also to be undertaken to increase muscle mass.
If weight loss results from a disease, resolving the illness and consuming adequate calories can bring many underweight individuals to a healthy body weight. | https://www.wikidoc.org/index.php/Underweight | |
5aae1c3ef68c57dc79f34a21145aa4b929a01e79 | wikidoc | Unit vector | Unit vector
In mathematics, a unit vector in a normed vector space is a vector (often a spatial vector) whose length is 1 (the unit length). A unit vector is often denoted by a lowercase letter with a superscribed caret or “hat”, like this: {\hat{\imath}} (pronounced "i-hat").
In Euclidean space, the dot product of two unit vectors is simply the cosine of the angle between them. This follows from the formula for the dot product, since the lengths are both 1.
The normalized vector or versor \boldsymbol{\hat{u}} of a non-zero vector \boldsymbol{u} is the unit vector codirectional with \boldsymbol{u}, i.e.,
where \|\boldsymbol{u}\| is the norm (or length) of \boldsymbol{u}. The term normalized vector is sometimes used as a synonym for unit vector.
The elements of a basis are usually chosen to be unit vectors. Every vector in the space may be written as a linear combination of unit vectors. The most commonly encountered bases are Cartesian, polar, and spherical coordinates. Each uses different unit vectors according to the symmetry of the coordinate system. Since these systems are encountered in so many different contexts, it is not uncommon to encounter different naming conventions than those used here.
# Cartesian coordinates
In the three-dimensional Cartesian coordinate system, the unit vectors codirectional with the x, y, and z axes are sometimes referred to as versors of the coordinate system.
These are often written using normal vector notation (e.g. i, or \vec{\imath}) rather than the caret notation, and in most contexts it can be assumed that i, j, and k, (or \vec{\imath}, \vec{\jmath}, and \vec{k}) are versors of a Cartesian coordinate system (hence a tern of reciprocally orthogonal unit vectors). The notations (\boldsymbol\hat{x}, \boldsymbol\hat{y}, \boldsymbol\hat{z}), (\boldsymbol\hat{x}_1, \boldsymbol\hat{x}_2, \boldsymbol\hat{x}_3), (\boldsymbol\hat{e}_x, \boldsymbol\hat{e}_y, \boldsymbol\hat{e}_z), or (\boldsymbol\hat{e}_1, \boldsymbol\hat{e}_2, \boldsymbol\hat{e}_3), with or without hat/caret, are also used, particularly in contexts where i, j, k might lead to confusion with another quantity (for instance with index symbols such as i, j, k, used to identify an element of a set or array or sequence of variables). These vectors represent an example of standard basis.
When a unit vector in space is expressed, with Cartesian notation, as a linear combination of i, j, k, its three scalar components can be referred to as "direction cosines". The value of each component is equal to the cosine of the angle formed by the unit vector with the respective basis vector. This is one of the methods used to describe the orientation (angular position) of a straight line, segment of straight line, oriented axis, or segment of oriented axis (vector).
# Cylindrical coordinates
The unit vectors appropriate to cylindrical symmetry are: \boldsymbol{\hat{s}} (also designated \boldsymbol{\hat{r}} or \boldsymbol{\hat \rho}), the distance from the axis of symmetry; \boldsymbol{\hat \phi}, the angle measured counterclockwise from the positive x-axis; and \boldsymbol{\hat{z}}. They are related to the Cartesian basis \hat{x}, \hat{y}, \hat{z} by:
It is important to note that \boldsymbol{\hat{s}} and \boldsymbol{\hat \phi} are functions of \phi, and are not constant in direction. When differentiating or integrating in cylindrical coordinates, these unit vectors themselves must also be operated on. For a more complete description, see Jacobian. The derivatives with respect to \phi are:
# Spherical coordinates
The unit vectors appropriate to spherical symmetry are: \boldsymbol{\hat{r}}, the radial distance from the origin; \boldsymbol{\hat{\phi}}, the angle in the x-y plane counterclockwise from the positive x-axis; and \boldsymbol{\hat \theta}, the angle from the positive z axis. To minimize degeneracy, the polar angle is usually taken 0\leq\theta\leq 180^\circ. It is especially important to note the context of any ordered triplet written in spherical coordinates, as the roles of \boldsymbol{\hat \phi} and \boldsymbol{\hat \theta} are often reversed. Here, the American naming convention is used. This leaves the azimuthal angle \phi defined the same as in cylindrical coordinates. The Cartesian relations are:
The spherical unit vectors depend on both \phi and \theta, and hence there are 5 possible non-zero derivates. For a more complete description, see Jacobian. The non-zero derivatives are:
# Curvilinear Coordinates
In general, a coordinate system may be uniquely specified using a number of linearly independent unit vectors \boldsymbol\hat{e}_n equal to the degrees of freedom of the space. For ordinary 3-space, these vectors may be denoted \boldsymbol{\hat{e}_1}, \boldsymbol{\hat{e}_2}, \boldsymbol{\hat{e}_3}. It is nearly always convenient to define the system to be orthonormal and right-handed:
\boldsymbol{\hat{e}_i} \cdot \boldsymbol{\hat{e}_j} = \delta_{ij}
\boldsymbol{\hat{e}_1} \cdot (\boldsymbol{\hat{e}_2} \times \boldsymbol{\hat{e}_3}) = 1
where δij is the Kronecker delta. | Unit vector
In mathematics, a unit vector in a normed vector space is a vector (often a spatial vector) whose length is 1 (the unit length). A unit vector is often denoted by a lowercase letter with a superscribed caret or “hat”, like this: <math>{\hat{\imath}}</math> (pronounced "i-hat").
In Euclidean space, the dot product of two unit vectors is simply the cosine of the angle between them. This follows from the formula for the dot product, since the lengths are both 1.
The normalized vector or versor <math>\boldsymbol{\hat{u}}</math> of a non-zero vector <math>\boldsymbol{u}</math> is the unit vector codirectional with <math>\boldsymbol{u}</math>, i.e.,
where <math>\|\boldsymbol{u}\|</math> is the norm (or length) of <math>\boldsymbol{u}</math>. The term normalized vector is sometimes used as a synonym for unit vector.
The elements of a basis are usually chosen to be unit vectors. Every vector in the space may be written as a linear combination of unit vectors. The most commonly encountered bases are Cartesian, polar, and spherical coordinates. Each uses different unit vectors according to the symmetry of the coordinate system. Since these systems are encountered in so many different contexts, it is not uncommon to encounter different naming conventions than those used here.
# Cartesian coordinates
In the three-dimensional Cartesian coordinate system, the unit vectors codirectional with the x, y, and z axes are sometimes referred to as versors of the coordinate system.
These are often written using normal vector notation (e.g. i, or <math>\vec{\imath}</math>) rather than the caret notation, and in most contexts it can be assumed that i, j, and k, (or <math>\vec{\imath}, \vec{\jmath},</math> and <math> \vec{k}</math>) are versors of a Cartesian coordinate system (hence a tern of reciprocally orthogonal unit vectors). The notations <math>(\boldsymbol\hat{x}, \boldsymbol\hat{y}, \boldsymbol\hat{z})</math>, <math>(\boldsymbol\hat{x}_1, \boldsymbol\hat{x}_2, \boldsymbol\hat{x}_3)</math>, <math>(\boldsymbol\hat{e}_x, \boldsymbol\hat{e}_y, \boldsymbol\hat{e}_z)</math>, or <math>(\boldsymbol\hat{e}_1, \boldsymbol\hat{e}_2, \boldsymbol\hat{e}_3)</math>, with or without hat/caret, are also used, particularly in contexts where i, j, k might lead to confusion with another quantity (for instance with index symbols such as i, j, k, used to identify an element of a set or array or sequence of variables). These vectors represent an example of standard basis.
When a unit vector in space is expressed, with Cartesian notation, as a linear combination of i, j, k, its three scalar components can be referred to as "direction cosines". The value of each component is equal to the cosine of the angle formed by the unit vector with the respective basis vector. This is one of the methods used to describe the orientation (angular position) of a straight line, segment of straight line, oriented axis, or segment of oriented axis (vector).
# Cylindrical coordinates
The unit vectors appropriate to cylindrical symmetry are: <math>\boldsymbol{\hat{s}}</math> (also designated <math>\boldsymbol{\hat{r}}</math> or <math>\boldsymbol{\hat \rho}</math>), the distance from the axis of symmetry; <math>\boldsymbol{\hat \phi}</math>, the angle measured counterclockwise from the positive x-axis; and <math>\boldsymbol{\hat{z}}</math>. They are related to the Cartesian basis <math>\hat{x}, \hat{y}, \hat{z}</math> by:
It is important to note that <math>\boldsymbol{\hat{s}}</math> and <math>\boldsymbol{\hat \phi}</math> are functions of <math>\phi</math>, and are not constant in direction. When differentiating or integrating in cylindrical coordinates, these unit vectors themselves must also be operated on. For a more complete description, see Jacobian. The derivatives with respect to <math>\phi</math> are:
# Spherical coordinates
The unit vectors appropriate to spherical symmetry are: <math>\boldsymbol{\hat{r}}</math>, the radial distance from the origin; <math>\boldsymbol{\hat{\phi}}</math>, the angle in the x-y plane counterclockwise from the positive x-axis; and <math>\boldsymbol{\hat \theta}</math>, the angle from the positive z axis. To minimize degeneracy, the polar angle is usually taken <math>0\leq\theta\leq 180^\circ</math>. It is especially important to note the context of any ordered triplet written in spherical coordinates, as the roles of <math>\boldsymbol{\hat \phi}</math> and <math>\boldsymbol{\hat \theta}</math> are often reversed. Here, the American naming convention is used. This leaves the azimuthal angle <math>\phi</math> defined the same as in cylindrical coordinates. The Cartesian relations are:
The spherical unit vectors depend on both <math>\phi</math> and <math>\theta</math>, and hence there are 5 possible non-zero derivates. For a more complete description, see Jacobian. The non-zero derivatives are:
# Curvilinear Coordinates
In general, a coordinate system may be uniquely specified using a number of linearly independent unit vectors <math>\boldsymbol\hat{e}_n</math> equal to the degrees of freedom of the space. For ordinary 3-space, these vectors may be denoted <math>\boldsymbol{\hat{e}_1}, \boldsymbol{\hat{e}_2}, \boldsymbol{\hat{e}_3}</math>. It is nearly always convenient to define the system to be orthonormal and right-handed:
<math>\boldsymbol{\hat{e}_i} \cdot \boldsymbol{\hat{e}_j} = \delta_{ij} </math>
<math>\boldsymbol{\hat{e}_1} \cdot (\boldsymbol{\hat{e}_2} \times \boldsymbol{\hat{e}_3}) = 1 </math>
where δij is the Kronecker delta. | https://www.wikidoc.org/index.php/Unit_vector | |
511557807bf1635e88253dc78f424cf5c0630405 | wikidoc | Unoprostone | Unoprostone
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# Overview
Unoprostone is a antiglaucoma, prostaglandin and ophthalmologic agent that is FDA approved for the treatment of for lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Common adverse reactions include increased hair growth of eyelash, abnormal vision, burning sensation in eye, disorder of eyelid, disorder of lacrimal system, dry eyes, hyperemia of surface of eye and itching of eye.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Open-Angle Glaucoma=
- Unoprostone Isopropyl ophthalmic solution 0.15% is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
- The recommended dosage is one drop in the affected eye(s) twice daily.
- Rescula may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If two drugs are used, they should be administered at least five (5) minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Unoprostone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Unoprostone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Unoprostone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Unoprostone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Unoprostone in pediatric patients.
# Contraindications
- Rescula is contraindicated in patients with hypersensitivity to unoprostone isopropyl or any other ingredient in this product.
# Warnings
- Unoprostone isopropyl ophthalmic solution may gradually increase the pigmentation of the iris. The pigmentation change is believed to be due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased pigmentation are not known. Iris color changes seen with administration of unoprostone isopropyl ophthalmic solution may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. Treatment with Rescula solution can be continued in patients who develop noticeably increased iris pigmentation.
- Patients who receive treatment with Rescula should be informed of the possibility of increased pigmentation.
- Unoprostone isopropyl has been reported to cause pigment changes (darkening) to periorbital pigmented tissues and eyelashes. The pigmentation is expected to increase as long as unoprostone isopropyl is administered, but has been reported to be reversible upon discontinuation of unoprostone isopropyl ophthalmic solution in most patients.
- Rescula should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.
- Macular edema, including cystoid macular edema, has been reported. Rescula should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
- To minimize contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products.
- Rescula contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes following its administration [see Patient Counseling Information.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- In clinical studies, the most common ocular adverse reactions with use of Rescula were burning/stinging, burning/stinging upon drug instillation, dry eyes, itching, increased length of eyelashes, and injection. These were reported in approximately 10–25% of patients. Approximately 10–14% of patients were observed to have an increase in the length of eyelashes (≥ 1 mm) at 12 months, while 7% of patients were observed to have a decrease in the length of eyelashes.
- Ocular adverse reactions occurring in approximately 5–10% of patients were abnormal vision, eyelid disorder, foreign body sensation, and lacrimation disorder.
- Ocular adverse reactions occurring in approximately 1–5% of patients were blepharitis, cataract, conjunctivitis, corneal lesion, discharge from the eye, eye hemorrhage, eye pain, keratitis, irritation, photophobia, and vitreous disorder.
- Other ocular adverse reactions reported in less than 1% of patients were acute elevated intraocular pressure, color blindness, corneal deposits, corneal edema, corneal opacity, diplopia, hyperpigmentation of the eyelid, increased number of eyelashes, iris hyperpigmentation, iritis, optic atrophy, ptosis, retinal hemorrhage, and visual field defect.
- The most frequently reported nonocular adverse reaction associated with the use of Rescula in the clinical trials was flu-like syndrome that was observed in approximately 6% of patients. Nonocular adverse reactions reported in the 1–5% of patients were accidental injury, allergic reaction, back pain, bronchitis, increased cough, diabetes mellitus, dizziness, headache, hypertension, insomnia, pharyngitis, pain, rhinitis, and sinusitis.
- The following adverse reactions have been identified during post-approval use of Rescula. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
- Voluntary reports of adverse reactions occurring with the use of Rescula include corneal erosion.
- There have been rare spontaneous reports with a different formulation of unoprostone isopropyl (0.12%) of chemosis, dry mouth, nausea, vomiting and palpitations.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Unoprostone in the drug label.
# Drug Interactions
There is limited information regarding Drug Interaction of Unoprostone in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There were no teratogenic effects observed in rats and rabbits up to 5 and 0.3 mg/kg/day (approximately 1,000 and 60 fold the recommended human dose of 0.005 mg/kg/day in the rat and rabbit, respectively). There was an increase in the incidence of miscarriages and a decrease in live birth index in rats administered unoprostone isopropyl during organogenesis at subcutaneous doses of 5 mg/kg. There was an increase in incidence of miscarriages and resorptions and a decrease in the number of live fetuses in rabbits administered unoprostone isopropyl during organogenesis at subcutaneous doses of 0.3 mg/kg. The no observable adverse effect level (NOAEL) for embryofetal toxicity in rats and rabbits was 2 and 0.1 mg/kg (approximately 400 and 20 fold the recommended human dose of 0.005 mg/kg/day in the rat and rabbit, respectively).
- There was an increase in incidence of premature delivery, a decrease in live birth index, and a decrease in weight at birth and through postpartum Day 7 in rats administered unoprostone isopropyl during late gestation through postpartum Day 21 at subcutaneous doses of 1.25 mg/kg. In addition, pups from rats administered 1.25 mg/kg subcutaneously exhibited delayed growth and development characterized by delayed incisor eruption and eye opening. There was an increase in the number of stillborn pups and a decrease in perinatal survival in rats administered unoprostone isopropyl during late gestation through weaning at subcutaneous doses of ≥ 0.5 mg/kg. The NOAEL for pre- and postnatal toxicity in rats was 0.2 mg/kg (approximately 40 fold the recommended human dose of 0.005 mg/kg/day).
- There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, Rescula should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Unoprostone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on the use of Unoprostone with respect to during labor and delivery.
### Nursing Mothers
- It is not known whether Rescula is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Rescula is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Unoprostone with respect to pediatric patients.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
### Gender
There is no FDA guidance on the use of Unoprostone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Unoprostone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Unoprostone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Unoprostone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Unoprostone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Unoprostone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Unoprostone Administration in the drug label.
### Monitoring
There is limited information regarding Monitoring of Unoprostone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Unoprostone in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Unoprostone in the drug label.
# Pharmacology
## Mechanism of Action
- Rescula is believed to reduce elevated intraocular pressure (IOP) by increasing the outflow of aqueous humor through the trabecular meshwork. Unoprostone isopropyl (UI) may have a local effect on BK (Big Potassium) channels and ClC-2 chloride channels, but the exact mechanism is unknown at this time.
## Structure
- Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is a synthetic docosanoid. Unoprostone isopropyl has the chemical name isopropyl (+)-(Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl-5-heptenoate. Its molecular formula is C25H44O5 and its chemical structure is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Unoprostone in the drug label.
## Pharmacokinetics
### Absorption=
- After application to the eye, unoprostone isopropyl is absorbed through the cornea and conjunctival epithelium where it is hydrolyzed by esterases to unoprostone free acid.
- A study conducted with 18 healthy volunteers dosed bilaterally with unoprostone isopropyl ophthalmic solution twice daily for 14 days demonstrated little systemic absorption of unoprostone isopropyl. The systemic exposure of its metabolite unoprostone free acid was minimal following the ocular administration. Mean peak unoprostone free acid concentration was less than 1.5 ng/mL. Little or no accumulation of unoprostone free acid was observed.
- Following ocular application, unoprostone isopropyl is hydrolyzed by esterases in the cornea to its biological active metabolite, unoprostone free acid. Unoprostone free acid is further metabolized to several inactive metabolites with lower molecular weight and increased polarity via ω- or β-oxidation. No secondary conjugation is found and no significant effect on hepatic microsomal enzyme activity has been observed.
- Elimination of unoprostone free acid from human plasma is rapid, with a half-life of 14 minutes. Plasma levels of unoprostone free acid dropped below the lower limit of quantitation (< 0.25 ng/mL) 1 hour following ocular instillation. The metabolites are excreted predominately in urine.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility=
- Unoprostone isopropyl was not carcinogenic in rats administered oral doses up to 12 mg/kg/day for up to 2 years (approximately 580 and 240 fold the recommended human dose of 0.005 mg/kg/day based on AUC0–24 in male and female rats, respectively).
- Under the conditions tested, unoprostone isopropyl and unoprostone free acid were neither mutagenic in an Ames assay nor clastogenic in a chromosome aberration assay in Chinese hamster lung–derived fibroblast cells. Under the conditions tested, unoprostone isopropyl was not genotoxic in a mouse lymphoma mutation assay or clastogenic in an in vivo chromosomal aberration test in mouse bone marrow.
- Unoprostone isopropyl did not impair male or female fertility in rats at subcutaneous doses up to 50 mg/kg (approximately 10,000 fold the recommended human dose of 0.005 mg/kg/day).
# Clinical Studies
- In six (6) month randomized controlled clinical studies in patients with a mean baseline intraocular pressure of 23 mmHg, Rescula lowered intraocular pressure by approximately 3–4 mmHg throughout the day. Rescula appeared to lower intraocular pressure without affecting cardiovascular or pulmonary function.
# How Supplied
- Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is supplied sterile in a low-density polyethylene bottle with a low-density polyethylene dropper tip, a turquoise polypropylene closure, and a clear tamper-evident shrinkband.
5 mL in a 7.5 mL bottle NDC 17350-015-05
## Storage
- Store between 2°–25°C (36°–77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed that the Rescula bottle must be maintained intact and to avoid allowing the tip of the bottle to contact surrounding structures, fingers, or any other unintended surface in order to avoid contamination of the bottle or applicator by common bacteria known to cause ocular infections. Serious infections may result from using contaminated solutions.
- Patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent.
- Patients should be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of Rescula.
- Patients should be advised that Rescula contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to application of Rescula and may be reinserted 15 minutes following its administration.
- If more than one topical ophthalmic therapy is being used patients should be instructed to administer the drugs at least 5 minutes apart.
# Precautions with Alcohol
- Alcohol-Unoprostone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Rescula®
# Look-Alike Drug Names
There is limited information regarding Unoprostone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Unoprostone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Unoprostone is a antiglaucoma, prostaglandin and ophthalmologic agent that is FDA approved for the treatment of for lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Common adverse reactions include increased hair growth of eyelash, abnormal vision, burning sensation in eye, disorder of eyelid, disorder of lacrimal system, dry eyes, hyperemia of surface of eye and itching of eye.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Open-Angle Glaucoma=
- Unoprostone Isopropyl ophthalmic solution 0.15% is indicated for the lowering of intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
- The recommended dosage is one drop in the affected eye(s) twice daily.
- Rescula may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If two drugs are used, they should be administered at least five (5) minutes apart.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Unoprostone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Unoprostone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Unoprostone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Unoprostone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Unoprostone in pediatric patients.
# Contraindications
- Rescula is contraindicated in patients with hypersensitivity to unoprostone isopropyl or any other ingredient in this product.
# Warnings
- Unoprostone isopropyl ophthalmic solution may gradually increase the pigmentation of the iris. The pigmentation change is believed to be due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased pigmentation are not known. Iris color changes seen with administration of unoprostone isopropyl ophthalmic solution may not be noticeable for several months to years. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. Treatment with Rescula solution can be continued in patients who develop noticeably increased iris pigmentation.
- Patients who receive treatment with Rescula should be informed of the possibility of increased pigmentation.
- Unoprostone isopropyl has been reported to cause pigment changes (darkening) to periorbital pigmented tissues and eyelashes. The pigmentation is expected to increase as long as unoprostone isopropyl is administered, but has been reported to be reversible upon discontinuation of unoprostone isopropyl ophthalmic solution in most patients.
- Rescula should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated.
- Macular edema, including cystoid macular edema, has been reported. Rescula should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.
- To minimize contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use. There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products.
- Rescula contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes following its administration [see Patient Counseling Information.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- In clinical studies, the most common ocular adverse reactions with use of Rescula were burning/stinging, burning/stinging upon drug instillation, dry eyes, itching, increased length of eyelashes, and injection. These were reported in approximately 10–25% of patients. Approximately 10–14% of patients were observed to have an increase in the length of eyelashes (≥ 1 mm) at 12 months, while 7% of patients were observed to have a decrease in the length of eyelashes.
- Ocular adverse reactions occurring in approximately 5–10% of patients were abnormal vision, eyelid disorder, foreign body sensation, and lacrimation disorder.
- Ocular adverse reactions occurring in approximately 1–5% of patients were blepharitis, cataract, conjunctivitis, corneal lesion, discharge from the eye, eye hemorrhage, eye pain, keratitis, irritation, photophobia, and vitreous disorder.
- Other ocular adverse reactions reported in less than 1% of patients were acute elevated intraocular pressure, color blindness, corneal deposits, corneal edema, corneal opacity, diplopia, hyperpigmentation of the eyelid, increased number of eyelashes, iris hyperpigmentation, iritis, optic atrophy, ptosis, retinal hemorrhage, and visual field defect.
- The most frequently reported nonocular adverse reaction associated with the use of Rescula in the clinical trials was flu-like syndrome that was observed in approximately 6% of patients. Nonocular adverse reactions reported in the 1–5% of patients were accidental injury, allergic reaction, back pain, bronchitis, increased cough, diabetes mellitus, dizziness, headache, hypertension, insomnia, pharyngitis, pain, rhinitis, and sinusitis.
- The following adverse reactions have been identified during post-approval use of Rescula. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
- Voluntary reports of adverse reactions occurring with the use of Rescula include corneal erosion.
- There have been rare spontaneous reports with a different formulation of unoprostone isopropyl (0.12%) of chemosis, dry mouth, nausea, vomiting and palpitations.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Unoprostone in the drug label.
# Drug Interactions
There is limited information regarding Drug Interaction of Unoprostone in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There were no teratogenic effects observed in rats and rabbits up to 5 and 0.3 mg/kg/day (approximately 1,000 and 60 fold the recommended human dose of 0.005 mg/kg/day in the rat and rabbit, respectively). There was an increase in the incidence of miscarriages and a decrease in live birth index in rats administered unoprostone isopropyl during organogenesis at subcutaneous doses of 5 mg/kg. There was an increase in incidence of miscarriages and resorptions and a decrease in the number of live fetuses in rabbits administered unoprostone isopropyl during organogenesis at subcutaneous doses of 0.3 mg/kg. The no observable adverse effect level (NOAEL) for embryofetal toxicity in rats and rabbits was 2 and 0.1 mg/kg (approximately 400 and 20 fold the recommended human dose of 0.005 mg/kg/day in the rat and rabbit, respectively).
- There was an increase in incidence of premature delivery, a decrease in live birth index, and a decrease in weight at birth and through postpartum Day 7 in rats administered unoprostone isopropyl during late gestation through postpartum Day 21 at subcutaneous doses of 1.25 mg/kg. In addition, pups from rats administered 1.25 mg/kg subcutaneously exhibited delayed growth and development characterized by delayed incisor eruption and eye opening. There was an increase in the number of stillborn pups and a decrease in perinatal survival in rats administered unoprostone isopropyl during late gestation through weaning at subcutaneous doses of ≥ 0.5 mg/kg. The NOAEL for pre- and postnatal toxicity in rats was 0.2 mg/kg (approximately 40 fold the recommended human dose of 0.005 mg/kg/day).
- There are no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, Rescula should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Unoprostone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on the use of Unoprostone with respect to during labor and delivery.
### Nursing Mothers
- It is not known whether Rescula is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Rescula is administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Unoprostone with respect to pediatric patients.
### Geriatic Use
- No overall differences in safety or effectiveness have been observed between elderly and other adult patients.
### Gender
There is no FDA guidance on the use of Unoprostone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Unoprostone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Unoprostone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Unoprostone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Unoprostone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Unoprostone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Unoprostone Administration in the drug label.
### Monitoring
There is limited information regarding Monitoring of Unoprostone in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Unoprostone in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Unoprostone in the drug label.
# Pharmacology
## Mechanism of Action
- Rescula is believed to reduce elevated intraocular pressure (IOP) by increasing the outflow of aqueous humor through the trabecular meshwork. Unoprostone isopropyl (UI) may have a local effect on BK (Big Potassium) channels and ClC-2 chloride channels, but the exact mechanism is unknown at this time.
## Structure
- Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is a synthetic docosanoid. Unoprostone isopropyl has the chemical name isopropyl (+)-(Z)-7-(1R,2R,3R,5S)-3,5-dihydroxy-2-(3-oxodecyl)cyclopentyl-5-heptenoate. Its molecular formula is C25H44O5 and its chemical structure is:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Unoprostone in the drug label.
## Pharmacokinetics
### Absorption=
- After application to the eye, unoprostone isopropyl is absorbed through the cornea and conjunctival epithelium where it is hydrolyzed by esterases to unoprostone free acid.
- A study conducted with 18 healthy volunteers dosed bilaterally with unoprostone isopropyl ophthalmic solution twice daily for 14 days demonstrated little systemic absorption of unoprostone isopropyl. The systemic exposure of its metabolite unoprostone free acid was minimal following the ocular administration. Mean peak unoprostone free acid concentration was less than 1.5 ng/mL. Little or no accumulation of unoprostone free acid was observed.
- Following ocular application, unoprostone isopropyl is hydrolyzed by esterases in the cornea to its biological active metabolite, unoprostone free acid. Unoprostone free acid is further metabolized to several inactive metabolites with lower molecular weight and increased polarity via ω- or β-oxidation. No secondary conjugation is found and no significant effect on hepatic microsomal enzyme activity has been observed.
- Elimination of unoprostone free acid from human plasma is rapid, with a half-life of 14 minutes. Plasma levels of unoprostone free acid dropped below the lower limit of quantitation (< 0.25 ng/mL) 1 hour following ocular instillation. The metabolites are excreted predominately in urine.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility=
- Unoprostone isopropyl was not carcinogenic in rats administered oral doses up to 12 mg/kg/day for up to 2 years (approximately 580 and 240 fold the recommended human dose of 0.005 mg/kg/day based on AUC0–24 in male and female rats, respectively).
- Under the conditions tested, unoprostone isopropyl and unoprostone free acid were neither mutagenic in an Ames assay nor clastogenic in a chromosome aberration assay in Chinese hamster lung–derived fibroblast cells. Under the conditions tested, unoprostone isopropyl was not genotoxic in a mouse lymphoma mutation assay or clastogenic in an in vivo chromosomal aberration test in mouse bone marrow.
- Unoprostone isopropyl did not impair male or female fertility in rats at subcutaneous doses up to 50 mg/kg (approximately 10,000 fold the recommended human dose of 0.005 mg/kg/day).
# Clinical Studies
- In six (6) month randomized controlled clinical studies in patients with a mean baseline intraocular pressure of 23 mmHg, Rescula lowered intraocular pressure by approximately 3–4 mmHg throughout the day. Rescula appeared to lower intraocular pressure without affecting cardiovascular or pulmonary function.
# How Supplied
- Rescula (unoprostone isopropyl ophthalmic solution) 0.15% is supplied sterile in a low-density polyethylene bottle with a low-density polyethylene dropper tip, a turquoise polypropylene closure, and a clear tamper-evident shrinkband.
5 mL in a 7.5 mL bottle NDC 17350-015-05
## Storage
- Store between 2°–25°C (36°–77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed that the Rescula bottle must be maintained intact and to avoid allowing the tip of the bottle to contact surrounding structures, fingers, or any other unintended surface in order to avoid contamination of the bottle or applicator by common bacteria known to cause ocular infections. Serious infections may result from using contaminated solutions.
- Patients should be advised about the potential for increased brown iris pigmentation which is likely to be permanent.
- Patients should be informed about the possibility of eyelid skin darkening, which may be reversible after discontinuation of Rescula.
- Patients should be advised that Rescula contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to application of Rescula and may be reinserted 15 minutes following its administration.
- If more than one topical ophthalmic therapy is being used patients should be instructed to administer the drugs at least 5 minutes apart.
# Precautions with Alcohol
- Alcohol-Unoprostone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Rescula®
# Look-Alike Drug Names
There is limited information regarding Unoprostone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Unoprostone | |
6df08db665bf8bedfdc8f72465bcb62c4849809d | wikidoc | Uranium-238 | Uranium-238
Uranium-238 (U-238), is the most common isotope of uranium found in nature. When hit by a neutron, it becomes uranium-239 (U-239), an unstable isotope which decays into neptunium-239 (Np-239), which then itself decays, with a half-life of 2.355 days, into plutonium-239 (Pu-239).
Around 99.284% of natural uranium is uranium-238, which has a half-life of 1.41 × 1017 seconds (4.46 × 109 years, or 4.46 billion years). Depleted uranium consists mainly of the 238 isotope, and enriched uranium has a higher-than-natural quantity of the uranium-235 isotope. Reprocessed uranium is also mainly U-238, but contains significant quantities of uranium-236, and in fact all the isotopes of uranium between uranium-232 and uranium-238 except uranium-237.
# Nuclear energy applications
In a nuclear reactor, uranium-238 can be used to breed plutonium-239, which itself can be used in a nuclear weapon or as a reactor fuel source. In fact, in a typical nuclear reactor, up to a third of the generated power does come from the fission of plutonium-239, which is not supplied as a fuel to the reactor, but transmuted from uranium-238.
## Breeder reactors
Uranium-238 is not usable directly as nuclear fuel; however, it can be used as a source material for creating the element plutonium. Breeder reactors carry out such a process of transmutation to convert fertile isotopes such as uranium-238 into fissile plutonium. It has been estimated that there is anywhere from 10,000 to five billion years worth of uranium-238 for use in these power plants . Breeder technology has been used in several reactors .
As of December 2005, the only breeder reactor producing power is the 600-megawatt BN-600 reactor at the Beloyarsk Nuclear Power Station in Russia. Russia has planned to build another unit, BN-800, at Beloyarsk nuclear power plant. Also, Japan's Monju breeder reactor is planned for restart, having been shut down since 1995, and both China and India have announced intentions to build breeder reactors.
The Clean And Environmentally Safe Advanced Reactor (CAESAR), a nuclear reactor concept that would use steam as a moderator to control delayed neutrons, will potentially be able to burn uranium-238 as fuel once the reactor is started with LEU fuel. This design is still in the early stages of development.
## Radiation shielding
Uranium-238 is also used as a radiation shield — its alpha radiation is easily stopped by the non-radioactive casing of the shielding and the uranium's high atomic weight and high number of electrons is highly effective in absorbing gamma rays and x-rays. However, it is not as effective as ordinary water for stopping fast neutrons. Both metallic depleted uranium and depleted uranium dioxide are being used as materials for radiation shielding. Uranium is about five times better as a gamma ray shield than lead, so a shield with the same effectivity can be packed into a thinner layer.
DUCRETE, a concrete made with uranium dioxide aggregate instead of gravel, is being investigated as a material for dry cask storage systems to store radioactive waste.
## Downblending
The opposite of enriching is downblending. Surplus highly-enriched uranium can be downblended with depleted uranium or natural uranium to turn it into low enriched uranium suitable for use in commercial nuclear fuel.
Uranium-238 from depleted uranium and natural uranium is also used with recycled plutonium from weapons stockpiles for making mixed oxide fuel (MOX) which is now being redirected to become reactor fuel. This dilution, also called downblending, means that any nation or group that acquired the finished fuel would have to repeat the very expensive and complex enrichment and separation processes before assembling a weapon.
# Nuclear weapons
Most modern nuclear weapons utilize uranium-238 as a "tamper" material (see nuclear weapon design). A tamper which surrounds a fissile core works to reflect neutrons and add inertia to the compression of the plutonium charge. As such, it increases the efficiency of the weapon and reduces the amount of critical mass required. In the case of a thermonuclear weapon uranium-238
can be used to encase the fusion fuel, the high flux of very energetic neutrons from the resulting fusion reaction causes the uranium-238 to fission and adds energy to the yield of the weapon. Such weapons are referred to as fission-fusion-fission weapons after the three consecutive stages of the explosion.
The larger portion of the total explosive yield in this design comes from the final fission stage fueled by uranium-238, producing enormous amounts of radioactive fission products. For example, 77% of the 10.4 megaton yield of the Ivy Mike thermonuclear test in 1952 came from fast fission of the depleted uranium tamper. Because depleted uranium has no critical mass, it can be added to thermonuclear bombs in almost unlimited quantity. The 1961 Soviet test of Tsar Bomba produced "only" 50 megatons, over 90% from fusion, because the uranium-238 final stage was replaced with lead. Had uranium-238 been used, the yield could have been as much as 100 megatons, and would have produced fallout equivalent to one third of the global total at that time.
# Radioactivity and decay
Uranium-238's decay product thorium-234 has a halflife of 246,000 years and so is useful for determining the age of sediments that are between 100,000 years and 1,200,000 years in age.
The mean lifetime of uranium-238 is 1.41 × 1017 seconds divided by 0.693 (or multiplied by 1.443), i.e. ca. 2 × 1017 seconds, so 1 mole of uranium-238 emits 3 × 106 alpha particles per second, producing the same number of thorium-234 (Th-234) atoms. In a closed system an equilibrium would be reached, with all amounts except lead-206 and uranium-238 in fixed ratios, in slowly decreasing amounts. The amount of Pb-206 will increase accordingly while U-238 decreases; all steps in the decay chain have this same rate of 3 × 106 decayed particles per second per mole uranium-238.
Thorium-234 has a mean lifetime of 3 × 106 seconds, so there is equilibrium if 1 mole of uranium-238 contains 9 × 1012 atoms of thorium-234, which is 1.5 × 10-11 mole (the ratio of the two half-lives). Similarly, in an equilibrium in a closed system the amount of each decay product, except the end product lead, is proportional to its half-life.
As already touched upon above, when starting with pure uranium-238, within a human timescale the equilibrium applies for the first three steps in the decay chain only. Thus, per mole of uranium-238, 3 × 106 times per second one alpha and two beta particles and gamma ray are produced, together 6.7 MeV, a rate of 3 µW. Extrapolated over 2 × 1017 seconds this is 600 GJ, the total energy released in the first three steps in the decay chain | Uranium-238
Template:Infobox isotope
Uranium-238 (U-238), is the most common isotope of uranium found in nature. When hit by a neutron, it becomes uranium-239 (U-239), an unstable isotope which decays into neptunium-239 (Np-239), which then itself decays, with a half-life of 2.355 days, into plutonium-239 (Pu-239).
Around 99.284% of natural uranium[1] is uranium-238, which has a half-life of 1.41 × 1017 seconds (4.46 × 109 years, or 4.46 billion years). Depleted uranium consists mainly of the 238 isotope, and enriched uranium has a higher-than-natural quantity of the uranium-235 isotope. Reprocessed uranium is also mainly U-238, but contains significant quantities of uranium-236, and in fact all the isotopes of uranium between uranium-232 and uranium-238 except uranium-237. [2]
# Nuclear energy applications
In a nuclear reactor, uranium-238 can be used to breed plutonium-239, which itself can be used in a nuclear weapon or as a reactor fuel source. In fact, in a typical nuclear reactor, up to a third of the generated power does come from the fission of plutonium-239, which is not supplied as a fuel to the reactor, but transmuted from uranium-238.
## Breeder reactors
Uranium-238 is not usable directly as nuclear fuel; however, it can be used as a source material for creating the element plutonium. Breeder reactors carry out such a process of transmutation to convert fertile isotopes such as uranium-238 into fissile plutonium. It has been estimated that there is anywhere from 10,000 to five billion years worth of uranium-238 for use in these power plants [1]. Breeder technology has been used in several reactors [2].
As of December 2005, the only breeder reactor producing power is the 600-megawatt BN-600 reactor at the Beloyarsk Nuclear Power Station in Russia. Russia has planned to build another unit, BN-800, at Beloyarsk nuclear power plant. Also, Japan's Monju breeder reactor is planned for restart, having been shut down since 1995, and both China and India have announced intentions to build breeder reactors.
The Clean And Environmentally Safe Advanced Reactor (CAESAR), a nuclear reactor concept that would use steam as a moderator to control delayed neutrons, will potentially be able to burn uranium-238 as fuel once the reactor is started with LEU fuel. This design is still in the early stages of development.
## Radiation shielding
Uranium-238 is also used as a radiation shield — its alpha radiation is easily stopped by the non-radioactive casing of the shielding and the uranium's high atomic weight and high number of electrons is highly effective in absorbing gamma rays and x-rays. However, it is not as effective as ordinary water for stopping fast neutrons. Both metallic depleted uranium and depleted uranium dioxide are being used as materials for radiation shielding. Uranium is about five times better as a gamma ray shield than lead, so a shield with the same effectivity can be packed into a thinner layer.
DUCRETE, a concrete made with uranium dioxide aggregate instead of gravel, is being investigated as a material for dry cask storage systems to store radioactive waste.
## Downblending
The opposite of enriching is downblending. Surplus highly-enriched uranium can be downblended with depleted uranium or natural uranium to turn it into low enriched uranium suitable for use in commercial nuclear fuel.
Uranium-238 from depleted uranium and natural uranium is also used with recycled plutonium from weapons stockpiles for making mixed oxide fuel (MOX) which is now being redirected to become reactor fuel. This dilution, also called downblending, means that any nation or group that acquired the finished fuel would have to repeat the very expensive and complex enrichment and separation processes before assembling a weapon.
# Nuclear weapons
Most modern nuclear weapons utilize uranium-238 as a "tamper" material (see nuclear weapon design). A tamper which surrounds a fissile core works to reflect neutrons and add inertia to the compression of the plutonium charge. As such, it increases the efficiency of the weapon and reduces the amount of critical mass required. In the case of a thermonuclear weapon uranium-238
can be used to encase the fusion fuel, the high flux of very energetic neutrons from the resulting fusion reaction causes the uranium-238 to fission and adds energy to the yield of the weapon. Such weapons are referred to as fission-fusion-fission weapons after the three consecutive stages of the explosion.
The larger portion of the total explosive yield in this design comes from the final fission stage fueled by uranium-238, producing enormous amounts of radioactive fission products. For example, 77% of the 10.4 megaton yield of the Ivy Mike thermonuclear test in 1952 came from fast fission of the depleted uranium tamper. Because depleted uranium has no critical mass, it can be added to thermonuclear bombs in almost unlimited quantity. The 1961 Soviet test of Tsar Bomba produced "only" 50 megatons, over 90% from fusion, because the uranium-238 final stage was replaced with lead. Had uranium-238 been used, the yield could have been as much as 100 megatons, and would have produced fallout equivalent to one third of the global total at that time.
# Radioactivity and decay
Uranium-238's decay product thorium-234 has a halflife of 246,000 years and so is useful for determining the age of sediments that are between 100,000 years and 1,200,000 years in age. [3]
Template:Radium series
The mean lifetime of uranium-238 is 1.41 × 1017 seconds divided by 0.693 (or multiplied by 1.443), i.e. ca. 2 × 1017 seconds, so 1 mole of uranium-238 emits 3 × 106 alpha particles per second, producing the same number of thorium-234 (Th-234) atoms. In a closed system an equilibrium would be reached, with all amounts except lead-206 and uranium-238 in fixed ratios, in slowly decreasing amounts. The amount of Pb-206 will increase accordingly while U-238 decreases; all steps in the decay chain have this same rate of 3 × 106 decayed particles per second per mole uranium-238.
Thorium-234 has a mean lifetime of 3 × 106 seconds, so there is equilibrium if 1 mole of uranium-238 contains 9 × 1012 atoms of thorium-234, which is 1.5 × 10-11 mole (the ratio of the two half-lives). Similarly, in an equilibrium in a closed system the amount of each decay product, except the end product lead, is proportional to its half-life.
As already touched upon above, when starting with pure uranium-238, within a human timescale the equilibrium applies for the first three steps in the decay chain only. Thus, per mole of uranium-238, 3 × 106 times per second one alpha and two beta particles and gamma ray are produced, together 6.7 MeV, a rate of 3 µW. Extrapolated over 2 × 1017 seconds this is 600 GJ, the total energy released in the first three steps in the decay chain
Template:Isotope | https://www.wikidoc.org/index.php/Uranium-238 | |
f97904a0f9b781a2e6f55e098f87286c882bf085 | wikidoc | Ureterocele | Ureterocele
For patient information page click here
Steven C. Campbell, M.D., Ph.D.
# Overview
A ureterocele is a congenital abnormality found in the urinary bladder. In this condition called ureteroceles, the distal ureter balloons at its opening into the bladder, forming a sac-like pouch. It is most often associated with a double collector system, where two ureters drain their respective kidney instead of one. Simple ureteroceles, where the condition involves only a single ureter, represents only twenty percent of cases.
Ureteroceles strikes only one in 4,000 individuals, at least four fifths of whom are female. Patients are frequently Caucasian.
# Causes
Definitive causes of ureteroceles have not been found. While the abnormal growth occurs within the uterus, it has not been substantiated that genetics are to blame.
# Signs and symptoms
The signs and symptoms of ureteroceles in the latter two forms can easily be confused with other medical conditions. Symptoms can include:
- Frequent urinary tract infection
- Urosepsis
- Obstructive voiding symptoms
- Urinary retention
- Failure to thrive
- Hematuria
- Cyclic abdominal pain
- Ureteral calculus
# Diagnosis
Since the advent of the ultrasound, most ureteroceles is diagnosed prenatally. The pediatric and adult conditions are often found only through diagnostic imaging performed for reasons other than suspicious ureteroceles.
## Imaging studies
- At US, the ureterocele is identified as a cystic intravesical mass contiguous with a dilated ureter.
- At VCUG, a collapsed simple ureterocele usually manifests as a rounded filling defect within the bladder.
- When performed, IVU will usually demonstrate a collection of contrast material within the ureterocele, which produces the classic cobra head sign consisting of a round or oval area of increased opacity surrounded by the radiolucent halo of the wall of the ureterocele.
Patient #1
Patient #2
# Complications
Many other complications arise from ureteroceles. Redundant collection systems are usually smaller in diameter than single, and predispose the patient to impassable kidney stones. The effective "bladder within a bladder" compounds this problem by increasing the collision of uric acid particles, the process by which uric acid stones are formed. Ureteroceles is also associated with poor kidney function. It can cause frequent blockage of the ureter leading to serious kidney damage. In other cases, a small, upper portion of the kidney is congenitally non-functional. Though often benign, this problem can necessitate the removal of non-functioning parts. | Ureterocele
For patient information page click here
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
A ureterocele is a congenital abnormality found in the urinary bladder. In this condition called ureteroceles, the distal ureter balloons at its opening into the bladder, forming a sac-like pouch. It is most often associated with a double collector system, where two ureters drain their respective kidney instead of one. Simple ureteroceles, where the condition involves only a single ureter, represents only twenty percent of cases.
Ureteroceles strikes only one in 4,000 individuals, at least four fifths of whom are female. Patients are frequently Caucasian.
# Causes
Definitive causes of ureteroceles have not been found. While the abnormal growth occurs within the uterus, it has not been substantiated that genetics are to blame.
# Signs and symptoms
The signs and symptoms of ureteroceles in the latter two forms can easily be confused with other medical conditions. Symptoms can include:
- Frequent urinary tract infection
- Urosepsis
- Obstructive voiding symptoms
- Urinary retention
- Failure to thrive
- Hematuria
- Cyclic abdominal pain
- Ureteral calculus
# Diagnosis
Since the advent of the ultrasound, most ureteroceles is diagnosed prenatally. The pediatric and adult conditions are often found only through diagnostic imaging performed for reasons other than suspicious ureteroceles.
## Imaging studies
- At US, the ureterocele is identified as a cystic intravesical mass contiguous with a dilated ureter.
- At VCUG, a collapsed simple ureterocele usually manifests as a rounded filling defect within the bladder.
- When performed, IVU will usually demonstrate a collection of contrast material within the ureterocele, which produces the classic cobra head sign consisting of a round or oval area of increased opacity surrounded by the radiolucent halo of the wall of the ureterocele.
Patient #1
-
-
-
-
Patient #2
-
-
# Complications
Many other complications arise from ureteroceles. Redundant collection systems are usually smaller in diameter than single, and predispose the patient to impassable kidney stones. The effective "bladder within a bladder" compounds this problem by increasing the collision of uric acid particles, the process by which uric acid stones are formed. Ureteroceles is also associated with poor kidney function. It can cause frequent blockage of the ureter leading to serious kidney damage. In other cases, a small, upper portion of the kidney is congenitally non-functional. Though often benign, this problem can necessitate the removal of non-functioning parts.
Template:Nephrology
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ureterocele | |
e74f69442d367ef63361c7827d4e159ebb30f321 | wikidoc | Urgent care | Urgent care
# Overview
Urgent care is the delivery of ambulatory care in a facility dedicated to the delivery of unscheduled, walk-in care outside of a hospital emergency department. Urgent care centers are primarily used to treat patients who have an injury or illness that requires immediate care but is not serious enough to warrant a visit to an emergency room. Often urgent care centers are not open on a continuous basis, unlike a hospital emergency room that would be open at all times.
The initial urgent care centers opened in the 1970s. Since then this sector of the healthcare industry has rapidly expanded to an approximately 17,000 centers. Many of these centers have been started by entrepreneurial physicians who have responded to the public need for convenient access to unscheduled medical care. Other centers have been opened by hospital systems, seeking to attract patients. Much of the growth of these centers has been fueled by the significant savings that urgent care centers provide over the care in a hospital emergency department. Many managed care organizations (MCOs) now encourage their customers to utilize the urgent care option.
# Other Ambulatory Healthcare Facilities
Urgent care centers are distinguished from other similar types of ambulatory healthcare centers.
## Emergency Departments
Emergency departments are located within hospitals and are prepared to care for patients suffering true emergencies, such as myocardial infarctions ("heart attacks"), serious motor vehicle accidents, suicide attempts, and other such life-threatening conditions. Being located within a hospital, these centers are positioned to provide ready access to major surgeries and critical care units. Emergency departments are usually staffed by physicians with specialized training or board certification in emergency medicine. Most states in the USA require all hospitals to house an emergency department within the hospital building. A few states in the USA allow freestanding emergency departments to be built outside of a hospital building. Many authorities would consider this type of facility to be a high-acuity urgent care center, rather than a true emergency department.
## Primary Care Offices with Extended Hours
Many primary care offices are open for some hours in the evenings and weekends. However, unless these centers are open for walk-in patients at all times when open for patients, offer on-site x-ray facilities, and care for most simple fractures and lacerations--these primary care physician offices are not considered to be true urgent care centers.
## Walk-In Primary Care Offices
Allowing walk-in patients is not a sufficient criterion to define a physician office as an urgent care. If the office does not offer the expanded services and significant after-hours care, then the physician office would not fit the definition of an urgent care center.
## Mid-level Provider Offices in Retail Stores
In 2004, medical treatment began to be offered at small offices in retail stores with onsite pharmacies. These centers are generally staffed with nurse practitioners or physician assistants. Prices are generally posted in public view and patients can do shopping while waiting. Some experts consider these medical treatment sites to be the wave of the future in light of consumer driven health plans such as Health Savings Accounts. These retail clinics are not true urgent care centers, because of the limited level of care that can be provided without a physician nor x-ray facilities on site. Concerns about conflict of interest and incentives to over-prescribe medications in a facility rented from a pharmacy have yet to be fully addressed by organized medicine or governmental agencies.
# Organized Medicine and Urgent Care
The Urgent Care Association of America (UCAOA) holds an annual spring convention and, also, offers an annual fall conference. The American Academy of Urgent Care Medicine (AAUCM) and the National Association for Ambulatory Urgent Care (NAFAC) hold a joint annual convention. Many leaders in the urgent care industry now eagerly anticipate the full establishment of urgent care as a fully-recognized specialty with fellowships and/or residencies that allow for proper training in the unique patient mix and patient presentations that are seen in urgent care centers.
# Codes for Urgent Care
In recent years the American Medical Association approved the code UCM (Urgent Care Medicine) for physicians to self-designate themselves as specializing in urgent care medicine, this code was developed with the assistance of the American Academy of Urgent Care Medicine. Services rendered in an urgent care center may be designated, using the place of service code -20 (POS -20) on the CMS-1500 form, as submitted to third-party payors. The Centers for Medicare & Medicaid Services (CMS) have designated two specific codes to apply to urgent care centers: S9083 (global fee for urgent care centers) and S9088 (services rendered in an urgent care center). Because of the complex nature of coding for urgent care centers, the Urgent Care Association of America (UCAOA) offers a specialized day-and-a-half advanced coding workshop for providers and coders as part of its annual fall conference.
# Postgraduate Fellowship Training
In 2006, the Urgent Care Association of America sponsored the first fellowship training program in urgent care medicine. This fellowship resulted from collaboration between the Department of Family Medicine University Hospitals of Cleveland / Case School of Medicine, the Urgent Care Association of America (UCAOA), and University Primary and Specialty Care Practices, Inc. in Cleveland, Ohio. The program is partially funded by an unrestricted grant of $30,000 from the Urgent Care Association of America to support the fellowship program. Physicians in the urgent care fellowship program receive training in the many disciplines that an urgent care physician needs to master. These disciplines include adult emergencies, pediatric emergencies, wound and injury evaluation and treatment, occupational medicine, urgent care procedures, and business aspects of the urgent care center. In 2007, the Urgent Care Association of America (UCAOA) sponsored a second fellowship opportunity through the University of Illinois. The one-year fellowships are open to graduates of accredited Family Medicine and Med/Peds residencies.
# Urgent Care Journals
The official publication of the Urgent Care Association of America (UCAOA) is the Journal of Urgent Care Medicine (JUCM). It is a monthly publication published specifically for professionals in the urgent care industry. A free subscription to JUCM is available to licensed physicians, who sign up at www.jucm.com. The American Academy of Urgent Care Medicine publishes the journal Urgent Care. The official publication of the American Academy of Urgent Care Medicine is the Urgent Care. It is a monthly publication published specifically for physicans, physician assistants and nurse practitioners in the urgent care industry. A free subscription to Urgent Care is available to licensed physicians, who sign up at .
# Point-of-Care Medication Dispensing
Point-of-Care dispensing enables healthcare practitioners in the urgent care setting to ensure that their patients receive their prescription prior to leaving the clinic. To offer this service to patients, urgent care centers need to partner with a point-of-care dispensing corporation.
# Specialized Services
One sign that the urgent care industry is truly emerging as an important sector of the healthcare industry has been the development of supporting industries with specialized urgent care products.
## Practice Management Software
Software developed just for urgent care has been developed.
## Group Purchasing Organization
Group purchasing organizations, focusing on the urgent care industry, have been formed. The concept of these GPOs is that they join hundreds of urgent care centers together to allow the type of price bargaining that previously was only available to hospitals.
## Medical Malpractice Insurance
Malpractice insurance offerings unique to the urgent care industry have begun to be widely discussed in light of the fact that many insurers do not recognize the reduced malpractice risk of urgent care centers. Insurers that recognize this reduced risk do not group urgent care centers with hospital emergency physicians and other high-risk specialties. Features of this type of insurance may include no charge for tail coverage when providers leave ("tail coverage" is coverage for malpractice claims which may arise after termination of a policy), 3-5 day approval of new providers, no additional premium when providers are added to the policy, per visit FTE rating, and lower premiums. | Urgent care
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Urgent care is the delivery of ambulatory care in a facility dedicated to the delivery of unscheduled, walk-in care outside of a hospital emergency department. Urgent care centers are primarily used to treat patients who have an injury or illness that requires immediate care but is not serious enough to warrant a visit to an emergency room. Often urgent care centers are not open on a continuous basis, unlike a hospital emergency room that would be open at all times.
The initial urgent care centers opened in the 1970s. Since then this sector of the healthcare industry has rapidly expanded to an approximately 17,000 centers. Many of these centers have been started by entrepreneurial physicians who have responded to the public need for convenient access to unscheduled medical care. Other centers have been opened by hospital systems, seeking to attract patients. Much of the growth of these centers has been fueled by the significant savings that urgent care centers provide over the care in a hospital emergency department. Many managed care organizations (MCOs) now encourage their customers to utilize the urgent care option.
# Other Ambulatory Healthcare Facilities
Urgent care centers are distinguished from other similar types of ambulatory healthcare centers.
## Emergency Departments
Emergency departments are located within hospitals and are prepared to care for patients suffering true emergencies, such as myocardial infarctions ("heart attacks"), serious motor vehicle accidents, suicide attempts, and other such life-threatening conditions. Being located within a hospital, these centers are positioned to provide ready access to major surgeries and critical care units. Emergency departments are usually staffed by physicians with specialized training or board certification in emergency medicine. Most states in the USA require all hospitals to house an emergency department within the hospital building. A few states in the USA allow freestanding emergency departments to be built outside of a hospital building. Many authorities would consider this type of facility to be a high-acuity urgent care center, rather than a true emergency department.
## Primary Care Offices with Extended Hours
Many primary care offices are open for some hours in the evenings and weekends. However, unless these centers are open for walk-in patients at all times when open for patients, offer on-site x-ray facilities, and care for most simple fractures and lacerations--these primary care physician offices are not considered to be true urgent care centers.
## Walk-In Primary Care Offices
Allowing walk-in patients is not a sufficient criterion to define a physician office as an urgent care. If the office does not offer the expanded services and significant after-hours care, then the physician office would not fit the definition of an urgent care center.
## Mid-level Provider Offices in Retail Stores
In 2004, medical treatment began to be offered at small offices in retail stores with onsite pharmacies. These centers are generally staffed with nurse practitioners or physician assistants. Prices are generally posted in public view and patients can do shopping while waiting. Some experts consider these medical treatment sites to be the wave of the future in light of consumer driven health plans such as Health Savings Accounts. These retail clinics are not true urgent care centers, because of the limited level of care that can be provided without a physician nor x-ray facilities on site. Concerns about conflict of interest and incentives to over-prescribe medications in a facility rented from a pharmacy have yet to be fully addressed by organized medicine or governmental agencies.
# Organized Medicine and Urgent Care
The Urgent Care Association of America (UCAOA) holds an annual spring convention and, also, offers an annual fall conference. The American Academy of Urgent Care Medicine (AAUCM) and the National Association for Ambulatory Urgent Care (NAFAC) hold a joint annual convention. Many leaders in the urgent care industry now eagerly anticipate the full establishment of urgent care as a fully-recognized specialty with fellowships and/or residencies that allow for proper training in the unique patient mix and patient presentations that are seen in urgent care centers.
# Codes for Urgent Care
In recent years the American Medical Association approved the code UCM (Urgent Care Medicine) for physicians to self-designate themselves as specializing in urgent care medicine, this code was developed with the assistance of the American Academy of Urgent Care Medicine. Services rendered in an urgent care center may be designated, using the place of service code -20 (POS -20) on the CMS-1500 form, as submitted to third-party payors. The Centers for Medicare & Medicaid Services (CMS) have designated two specific codes to apply to urgent care centers: S9083 (global fee for urgent care centers) and S9088 (services rendered in an urgent care center). Because of the complex nature of coding for urgent care centers, the Urgent Care Association of America (UCAOA) offers a specialized day-and-a-half advanced coding workshop for providers and coders as part of its annual fall conference.
# Postgraduate Fellowship Training
In 2006, the Urgent Care Association of America sponsored the first fellowship training program in urgent care medicine. This fellowship resulted from collaboration between the Department of Family Medicine University Hospitals of Cleveland / Case School of Medicine, the Urgent Care Association of America (UCAOA), and University Primary and Specialty Care Practices, Inc. in Cleveland, Ohio. The program is partially funded by an unrestricted grant of $30,000 from the Urgent Care Association of America to support the fellowship program. Physicians in the urgent care fellowship program receive training in the many disciplines that an urgent care physician needs to master. These disciplines include adult emergencies, pediatric emergencies, wound and injury evaluation and treatment, occupational medicine, urgent care procedures, and business aspects of the urgent care center. In 2007, the Urgent Care Association of America (UCAOA) sponsored a second fellowship opportunity through the University of Illinois. The one-year fellowships are open to graduates of accredited Family Medicine and Med/Peds residencies.
# Urgent Care Journals
The official publication of the Urgent Care Association of America (UCAOA) is the Journal of Urgent Care Medicine (JUCM). It is a monthly publication published specifically for professionals in the urgent care industry. A free subscription to JUCM is available to licensed physicians, who sign up at www.jucm.com. The American Academy of Urgent Care Medicine publishes the journal Urgent Care. The official publication of the American Academy of Urgent Care Medicine is the Urgent Care. It is a monthly publication published specifically for physicans, physician assistants and nurse practitioners in the urgent care industry. A free subscription to Urgent Care is available to licensed physicians, who sign up at [urgentcarejournal.com].
# Point-of-Care Medication Dispensing
Point-of-Care dispensing enables healthcare practitioners in the urgent care setting to ensure that their patients receive their prescription prior to leaving the clinic. To offer this service to patients, urgent care centers need to partner with a point-of-care dispensing corporation.
# Specialized Services
One sign that the urgent care industry is truly emerging as an important sector of the healthcare industry has been the development of supporting industries with specialized urgent care products.
## Practice Management Software
Software developed just for urgent care has been developed.
## Group Purchasing Organization
Group purchasing organizations, focusing on the urgent care industry, have been formed. The concept of these GPOs is that they join hundreds of urgent care centers together to allow the type of price bargaining that previously was only available to hospitals.
## Medical Malpractice Insurance
Malpractice insurance offerings unique to the urgent care industry have begun to be widely discussed in light of the fact that many insurers do not recognize the reduced malpractice risk of urgent care centers. Insurers that recognize this reduced risk do not group urgent care centers with hospital emergency physicians and other high-risk specialties. Features of this type of insurance may include no charge for tail coverage when providers leave ("tail coverage" is coverage for malpractice claims which may arise after termination of a policy), 3-5 day approval of new providers, no additional premium when providers are added to the policy, per visit FTE rating, and lower premiums.
# External Links
- Homepage of the American Academy of Urgent Care Medicine
- Homepage of the Urgent Care Journal
- Homepage of the National Association For Ambulatory Care
- Homepage of the Urgent Care Association of America
- Homepage of the Journal of Urgent Care Medicine (JUCM) | https://www.wikidoc.org/index.php/Urgent_care | |
b5df7ef3ef3e291f711c8be9f83e6c703c3d6f07 | wikidoc | Urodynamics | Urodynamics
Steven C. Campbell, M.D., Ph.D.
# Overview
Urodynamics is the investigation of functional disorders of the lower urinary tract, i.e. the bladder and the urethra. Symptoms are particularly unreliable in the study of the lower urinary tract, so the purpose of urodynamics is to confirm objectively the pathology that a person's symptoms would suggest.
So for example if a person complains of a high frequency of urination it might be because of detrusor overactivity. Urodynamics would involve the use of pressure transducers attached to catheters inside the bladder and rectum to verify such a pressure pattern.
Detrusor overactivity is characterised by the phasic pressure contractions seen in the image on the right. The red trace is the abdominal pressure usually recorded in the rectum, the blue trace is the actual bladder pressure (usually called intravesical) and the purple trace is the detrusor pressure - the part of the intravesical pressure that is entirely due to the detrusor muscle. This is not a normal finding. The normal bladder should be low pressure during filling. | Urodynamics
Template:Search infobox
Steven C. Campbell, M.D., Ph.D.
# Overview
Urodynamics is the investigation of functional disorders of the lower urinary tract, i.e. the bladder and the urethra. Symptoms are particularly unreliable in the study of the lower urinary tract, so the purpose of urodynamics is to confirm objectively the pathology that a person's symptoms would suggest.
So for example if a person complains of a high frequency of urination it might be because of detrusor overactivity. Urodynamics would involve the use of pressure transducers attached to catheters inside the bladder and rectum to verify such a pressure pattern.
Detrusor overactivity is characterised by the phasic pressure contractions seen in the image on the right. The red trace is the abdominal pressure usually recorded in the rectum, the blue trace is the actual bladder pressure (usually called intravesical) and the purple trace is the detrusor pressure - the part of the intravesical pressure that is entirely due to the detrusor muscle. This is not a normal finding. The normal bladder should be low pressure during filling.
# External links
- Doug Small's urodynamic pages
- Basic Urodynamic Procedures
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Urodynamics | |
09835bb703fced21e29e7eed490887bc47ff4749 | wikidoc | Ustekinumab | Ustekinumab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Ustekinumab is a monoclonal antibody that is FDA approved for the {{{indicationType}}} of moderate to severe plaque psoriasis (Ps), active psoriatic arthritis (PsA). Common adverse reactions include nasopharyngitis, upper respiratory tract infection, headache, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
- Dosing Information
- The recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- For patients with co-existent moderate-to-severe plaque psoriasis weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ustekinumab in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Ustekinumab 6 mg/kg IV
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ustekinumab in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ustekinumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ustekinumab in pediatric patients.
# Contraindications
- Clinically significant hypersensitivity to ustekinumab or to any of the excipients.
# Warnings
### Precautions
- Infections
- STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA®.
- STELARA® should not be given to patients with any clinically important active infection. STELARA® should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA® in patients with a chronic infection or a history of recurrent infection.
- Serious infections requiring hospitalization occurred in the psoriasis and psoriatic arthritis development programs. In the psoriasis program, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In the psoriatic arthritis program, serious infections included cholecystitis.
- Theoretical Risk for Vulnerability to Particular Infections
- Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.
- It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances.
- Pre-treatment Evaluation for Tuberculosis
- Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA®.
- Do not administer STELARA® to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti-tuberculosis therapy prior to initiation of STELARA® in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA® should be monitored closely for signs and symptoms of active tuberculosis during and after treatment.
- Malignancies
- STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA® in clinical studies. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy.
- The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
- There have been post marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had pre-existing risk factors for developing non-melanoma skin cancer. All patients receiving STELARA® should be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment should be followed closely.
- Hypersensitivity Reactions
- Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported post-marketing. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®.
- Reversible Posterior Leukoencephalopathy Syndrome
- One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in the clinical trial safety databases for psoriasis and psoriatic arthritis. The subject, who had received 12 doses of STELARA® over approximately two years, presented with headache, seizures and confusion. No additional STELARA® injections were administered and the subject fully recovered with appropriate treatment..
- RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported.
- If RPLS is suspected, administer appropriate treatment and discontinue STELARA®.
- Immunizations
- Prior to initiating therapy with STELARA®, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA® or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA® because of the potential risk for shedding from the household contact and transmission to patient.
- Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.
- Concomitant Therapies
- In psoriasis studies the safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Psoriasis Clinical Studies
- The safety data reflect exposure to STELARA® in 3117 psoriasis subjects, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years.
- Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2
- Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).
- One case of RPLS occurred during clinical trials.
- Infections
- In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up).
- In the controlled and non-controlled portions of psoriasis clinical trials (median follow up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).
- Malignancies
- In the controlled and non-controlled portions of psoriasis clinical trials (median follow up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 per hundred subject-years of follow-up). The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1
- Psoriatic Arthritis Clinical Studies
- The safety of STELARA® was assessed in 927 patients in two randomized, double-blind, placebo-controlled studies in adult patients with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in patients with PsA was consistent with the safety profile seen in psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated patients when compared with placebo-treated patients (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.
- Immunogenicity
- Approximately 6% of patients treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. No ustekinumab-related serious hypersensitivity reactions were observed in psoriasis and psoriatic arthritis clinical trials. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.
- The data above reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- Adverse reactions have been reported during post-approval use with STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure.
- Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria).
- Skin reactions: Pustular psoriasis, erythrodermic psoriasis.
# Drug Interactions
- Concomitant Therapies
- In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®.
- CYP450 Substrates
- The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed.
- Allergen Immunotherapy
- STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There is a pregnancy registry that monitors pregnancy outcomes in women exposed to STELARA® during pregnancy. Patients should be encouraged to enroll by calling 1-877-311-8972.
- There are no adequate and well controlled studies of STELARA® in pregnant women. Developmental toxicity studies conducted with monkeys found no evidence of harm to the fetus due to ustekinumab. STELARA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Ustekinumab was tested in two embryo-fetal development toxicity studies with cynomolgus monkeys. No teratogenic effects or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections at doses up to 45 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 45 mg/kg).
- In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly up to 45 times the MRHD (on a mg/kg basis at a maternal dose of 45 mg/kg) from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ustekinumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ustekinumab during labor and delivery.
### Nursing Mothers
- Caution should be exercised when STELARA® is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA® will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts.
### Pediatric Use
There is no FDA guidance on the use of Ustekinumab with respect to pediatric patients.
### Geriatic Use
- Of the 4031 subjects exposed to STELARA®, a total of 248 were 65 years or older (183 patients with psoriasis and 65 patients with psoriatic arthritis), and 29 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ustekinumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ustekinumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ustekinumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ustekinumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ustekinumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ustekinumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Ustekinumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ustekinumab in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity.
### Management
- In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ustekinumab in the drug label.
# Pharmacology
## Mechanism of Action
- Ustekinumab is a human IgG1κ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1.
## Structure
- STELARA® is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, STELARA® is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. The manufacturing process contains steps for the clearance of viruses. STELARA® is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.
- STELARA®, for subcutaneous use, is available as: 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL. STELARA® is supplied as a sterile solution in a single-use prefilled syringe with a 27 gauge fixed ½ inch needle, or a single-use 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that is manufactured using a dry natural rubber (a derivative of latex).
- Each 45 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL.
- Each 90 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL.
- Each 45 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL.
- Each 90 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL.
- The STELARA® solution is colorless to slightly yellow in appearance and has a pH of 5.7–6.3. STELARA® does not contain preservatives.
## Pharmacodynamics
- In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with psoriasis.
## Pharmacokinetics
- Absorption
- In subjects with psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with psoriasis. Following multiple subcutaneous doses of STELARA®, the steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
- Distribution
- Following subcutaneous administration of 45 mg (N=18) and 90 mg (N=21) of ustekinumab to subjects with psoriasis, the mean (±SD) apparent volume of distribution during the terminal phase (Vz/F) was 161 ± 65 mL/kg and 179 ± 85 mL/kg, respectively. The mean (±SD) volume of distribution during the terminal phase (Vz) following a single intravenous administration to subjects with psoriasis ranged from 56.1 ± 6.5 to 82.1 ± 23.6 mL/kg.
- Metabolism
- The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
- Elimination
- The mean (±SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to subjects with psoriasis ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day/kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.
- Weight
- When given the same dose, subjects with psoriasis or psoriatic arthritis weighing >100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing ≤100 kg. The median trough serum concentrations of ustekinumab in subjects of higher weight (>100 kg) in the 90 mg group were comparable to those in subjects of lower weight (≤100 kg) in the 45 mg group.
- Hepatic and Renal Impairment
- No pharmacokinetic data are available in patients with hepatic or renal impairment.
- Elderly
- A population pharmacokinetic analysis (N=106/1937 subjects greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
- Drug-Drug Interactions
- The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance of in vitro data has not been established.
- Population pharmacokinetic data analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to anti-TNFα agents in patients with psoriatic arthritis.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA®. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.
- No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females.
- No effects on fertility were observed in female mice that were administered an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.
- In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.
# Clinical Studies
- Psoriasis
- Two multicenter, randomized, double-blind, placebo-controlled studies (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the studies.
- Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA® (either 45 mg or 90 mg) at Weeks 12 and 16.
- In both studies, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.
- In both studies, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of study subjects had a history of psoriatic arthritis.
- Clinical Response
- The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 2 below.
- Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups.
- In subjects who weighed ≤100 kg, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed >100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 3 below).
- Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
- Psoriatic Arthritis
- The safety and efficacy of STELARA® was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled studies in adult patients 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients, respectively, had enthesitis and dactylitis at baseline.
- Patients were randomized to receive treatment with STELARA® 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of patients achieving ACR 20 response at Week 24.
- In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the patients had been previously treated with an anti-TNFα agent, of whom over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance at any time.
- Clinical Response
- In both studies, a greater proportion of patients achieved ACR 20, ACR 50 and PASI 75 response in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 4). ACR 70 responses were also higher in the STELARA® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in Study 2. Responses were similar in patients regardless of prior TNFα exposure.
- The percent of patients achieving ACR 20 responses by visit is shown in Figure 1.
- Figure 1: Percent of patients achieving ACR 20 response through Week 24
- The results of the components of the ACR response criteria are shown in Table 5.
- An improvement in enthesitis and dactylitis scores was observed in each STELARA® group compared with placebo at Week 24.
- Physical Function
- STELARA® treated patients showed improvement in physical function compared to patients treated with placebo as assessed by HAQ-DI at Week 24. In both studies, the proportion of HAQ-DI responders (≥0.3 improvement in HAQ-DI score) was greater in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24.
# How Supplied
- STELARA® does not contain preservatives. STELARA® is available in single-use prefilled syringes or single-use vials containing 45 mg or 90 mg of ustekinumab. Each prefilled syringe is equipped with a needle safety guard.
- The NDC number for the 45 mg prefilled syringe is 57894-060-03.
- The NDC number for the 90 mg prefilled syringe is 57894-061-03.
- The NDC number for the 45 mg vial is 57894-060-02.
- The NDC number for the 90 mg vial is 57894-061-02.
- Storage and Stability
- STELARA® vials and prefilled syringes must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF). Store STELARA® vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. STELARA® does not contain a preservative; discard any unused portion.
## Storage
There is limited information regarding Ustekinumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to read the Medication Guide before starting STELARA® therapy and to reread the Medication Guide each time the prescription is renewed.
- Infections
- Inform patients that STELARA® may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection.
- Malignancies
- Patients should be counseled about the risk of malignancies while receiving STELARA®.
- Allergic Reactions
- Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions.
- Instruction on Injection Technique
- The first self-injection should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer STELARA®, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of STELARA®.
- Patients should be instructed to inject the full amount of STELARA® according to the directions provided in the Medication Guide and Instructions for Use. The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
- Needles and syringes should be disposed of in a puncture-resistant container. Patients or caregivers should be instructed in the technique of proper syringe and needle disposal, and be advised not to reuse these items.
# Precautions with Alcohol
- Alcohol-Ustekinumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Stelara®
# Look-Alike Drug Names
There is limited information regarding Ustekinumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ustekinumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Ustekinumab is a monoclonal antibody that is FDA approved for the {{{indicationType}}} of moderate to severe plaque psoriasis (Ps), active psoriatic arthritis (PsA). Common adverse reactions include nasopharyngitis, upper respiratory tract infection, headache, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
- Dosing Information
- The recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks.
- For patients with co-existent moderate-to-severe plaque psoriasis weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ustekinumab in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Ustekinumab 6 mg/kg IV[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ustekinumab in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ustekinumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ustekinumab in pediatric patients.
# Contraindications
- Clinically significant hypersensitivity to ustekinumab or to any of the excipients.
# Warnings
### Precautions
- Infections
- STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA®.
- STELARA® should not be given to patients with any clinically important active infection. STELARA® should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA® in patients with a chronic infection or a history of recurrent infection.
- Serious infections requiring hospitalization occurred in the psoriasis and psoriatic arthritis development programs. In the psoriasis program, serious infections included diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections. In the psoriatic arthritis program, serious infections included cholecystitis.
- Theoretical Risk for Vulnerability to Particular Infections
- Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients.
- It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA® will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances.
- Pre-treatment Evaluation for Tuberculosis
- Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA®.
- Do not administer STELARA® to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA®. Consider anti-tuberculosis therapy prior to initiation of STELARA® in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA® should be monitored closely for signs and symptoms of active tuberculosis during and after treatment.
- Malignancies
- STELARA® is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA® in clinical studies. In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy.
- The safety of STELARA® has not been evaluated in patients who have a history of malignancy or who have a known malignancy.
- There have been post marketing reports of the rapid appearance of multiple cutaneous squamous cell carcinomas in patients receiving STELARA® who had pre-existing risk factors for developing non-melanoma skin cancer. All patients receiving STELARA® should be monitored for the appearance of non-melanoma skin cancer. Patients greater than 60 years of age, those with a medical history of prolonged immunosuppressant therapy and those with a history of PUVA treatment should be followed closely.
- Hypersensitivity Reactions
- Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported post-marketing. If an anaphylactic or other clinically significant hypersensitivity reaction occurs, institute appropriate therapy and discontinue STELARA®.
- Reversible Posterior Leukoencephalopathy Syndrome
- One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed in the clinical trial safety databases for psoriasis and psoriatic arthritis. The subject, who had received 12 doses of STELARA® over approximately two years, presented with headache, seizures and confusion. No additional STELARA® injections were administered and the subject fully recovered with appropriate treatment..
- RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported.
- If RPLS is suspected, administer appropriate treatment and discontinue STELARA®.
- Immunizations
- Prior to initiating therapy with STELARA®, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA® should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA® or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA® because of the potential risk for shedding from the household contact and transmission to patient.
- Non-live vaccinations received during a course of STELARA® may not elicit an immune response sufficient to prevent disease.
- Concomitant Therapies
- In psoriasis studies the safety of STELARA® in combination with other immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Psoriasis Clinical Studies
- The safety data reflect exposure to STELARA® in 3117 psoriasis subjects, including 2414 exposed for at least 6 months, 1855 exposed for at least one year, 1653 exposed for at least two years, 1569 exposed for at least three years, 1482 exposed for at least four years and 838 exposed for at least five years.
- Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the STELARA® groups than the placebo group during the placebo-controlled period of Ps STUDY 1 and Ps STUDY 2
- Adverse reactions that occurred at rates less than 1% in the controlled period of Ps STUDIES 1 and 2 through week 12 included: cellulitis, herpes zoster, diverticulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation).
- One case of RPLS occurred during clinical trials.
- Infections
- In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA®-treated subjects), 27% of STELARA®-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA®-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up).
- In the controlled and non-controlled portions of psoriasis clinical trials (median follow up of 3.2 years), representing 8998 subject-years of exposure, 72.3% of STELARA®-treated subjects reported infections (0.87 per subject-years of follow-up). Serious infections were reported in 2.8% of subjects (0.01 per subject-years of follow-up).
- Malignancies
- In the controlled and non-controlled portions of psoriasis clinical trials (median follow up of 3.2 years, representing 8998 subject-years of exposure), 1.7% of STELARA®-treated subjects reported malignancies excluding non-melanoma skin cancers (0.60 per hundred subject-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of STELARA®-treated subjects (0.52 per hundred subject-years of follow-up). The most frequently observed malignancies other than non-melanoma skin cancer during the clinical trials were: prostate, melanoma, colorectal and breast. Malignancies other than non-melanoma skin cancer in STELARA®-treated patients during the controlled and uncontrolled portions of studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender and race).1
- Psoriatic Arthritis Clinical Studies
- The safety of STELARA® was assessed in 927 patients in two randomized, double-blind, placebo-controlled studies in adult patients with active psoriatic arthritis (PsA). The overall safety profile of STELARA® in patients with PsA was consistent with the safety profile seen in psoriasis clinical studies. A higher incidence of arthralgia, nausea, and dental infections was observed in STELARA®-treated patients when compared with placebo-treated patients (3% vs. 1% for arthralgia and 3% vs. 1% for nausea; 1% vs. 0.6% for dental infections) in the placebo-controlled portions of the PsA clinical trials.
- Immunogenicity
- Approximately 6% of patients treated with STELARA® in psoriasis and psoriatic arthritis clinical studies developed antibodies to ustekinumab, which were generally low-titer. No apparent association between the development of antibodies to ustekinumab and the development of injection site reactions was seen. No ustekinumab-related serious hypersensitivity reactions were observed in psoriasis and psoriatic arthritis clinical trials. In psoriasis studies, the majority of patients who were positive for antibodies to ustekinumab had neutralizing antibodies.
- The data above reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
- Adverse reactions have been reported during post-approval use with STELARA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to STELARA® exposure.
- Immune system disorders: Serious hypersensitivity reactions (including anaphylaxis and angioedema), other hypersensitivity reactions (including rash and urticaria).
- Skin reactions: Pustular psoriasis, erythrodermic psoriasis.
# Drug Interactions
- Concomitant Therapies
- In psoriasis studies the safety of STELARA® in combination with immunosuppressive agents or phototherapy has not been evaluated. In psoriatic arthritis studies, concomitant MTX use did not appear to influence the safety or efficacy of STELARA®.
- CYP450 Substrates
- The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, STELARA®, an antagonist of IL-12 and IL-23, could normalize the formation of CYP450 enzymes. Upon initiation of STELARA® in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed.
- Allergen Immunotherapy
- STELARA® has not been evaluated in patients who have undergone allergy immunotherapy. STELARA® may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients receiving or who have received allergen immunotherapy, particularly for anaphylaxis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There is a pregnancy registry that monitors pregnancy outcomes in women exposed to STELARA® during pregnancy. Patients should be encouraged to enroll by calling 1-877-311-8972.
- There are no adequate and well controlled studies of STELARA® in pregnant women. Developmental toxicity studies conducted with monkeys found no evidence of harm to the fetus due to ustekinumab. STELARA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Ustekinumab was tested in two embryo-fetal development toxicity studies with cynomolgus monkeys. No teratogenic effects or other adverse developmental effects were observed in fetuses from pregnant monkeys that were administered ustekinumab during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections at doses up to 45 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 45 mg/kg).
- In a combined embryo-fetal development and pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered subcutaneous doses of ustekinumab twice weekly up to 45 times the MRHD (on a mg/kg basis at a maternal dose of 45 mg/kg) from the beginning of organogenesis to Day 33 after delivery. Neonatal deaths occurred in the offspring of one monkey administered ustekinumab at 22.5 mg/kg and one monkey dosed at 45 mg/kg. No ustekinumab-related effects on functional, morphological, or immunological development were observed in the neonates from birth through six months of age.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ustekinumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ustekinumab during labor and delivery.
### Nursing Mothers
- Caution should be exercised when STELARA® is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA® will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts.
### Pediatric Use
There is no FDA guidance on the use of Ustekinumab with respect to pediatric patients.
### Geriatic Use
- Of the 4031 subjects exposed to STELARA®, a total of 248 were 65 years or older (183 patients with psoriasis and 65 patients with psoriatic arthritis), and 29 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ustekinumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ustekinumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ustekinumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ustekinumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ustekinumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ustekinumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Ustekinumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Ustekinumab in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Single doses up to 6 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity.
### Management
- In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Ustekinumab in the drug label.
# Pharmacology
## Mechanism of Action
- Ustekinumab is a human IgG1κ monoclonal antibody that binds with specificity to the p40 protein subunit used by both the IL-12 and IL-23 cytokines. IL-12 and IL-23 are naturally occurring cytokines that are involved in inflammatory and immune responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. In in vitro models, ustekinumab was shown to disrupt IL-12 and IL-23 mediated signaling and cytokine cascades by disrupting the interaction of these cytokines with a shared cell-surface receptor chain, IL-12Rβ1.
## Structure
- STELARA® is a human IgG1κ monoclonal antibody against the p40 subunit of the IL-12 and IL-23 cytokines. Using DNA recombinant technology, STELARA® is produced in a well characterized recombinant cell line and is purified using standard bio-processing technology. The manufacturing process contains steps for the clearance of viruses. STELARA® is comprised of 1326 amino acids and has an estimated molecular mass that ranges from 148,079 to 149,690 Daltons.
- STELARA®, for subcutaneous use, is available as: 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL. STELARA® is supplied as a sterile solution in a single-use prefilled syringe with a 27 gauge fixed ½ inch needle, or a single-use 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that is manufactured using a dry natural rubber (a derivative of latex).
- Each 45 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL.
- Each 90 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL.
- Each 45 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), Polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL.
- Each 90 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), Polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL.
- The STELARA® solution is colorless to slightly yellow in appearance and has a pH of 5.7–6.3. STELARA® does not contain preservatives.
## Pharmacodynamics
- In a small exploratory study, a decrease was observed in the expression of mRNA of its molecular targets IL-12 and IL-23 in lesional skin biopsies measured at baseline and up to two weeks post-treatment in subjects with psoriasis.
## Pharmacokinetics
- Absorption
- In subjects with psoriasis, the median time to reach the maximum serum concentration (Tmax) was 13.5 days and 7 days, respectively, after a single subcutaneous administration of 45 mg (N=22) and 90 mg (N=24) of ustekinumab. In healthy subjects (N=30), the median Tmax value (8.5 days) following a single subcutaneous administration of 90 mg of ustekinumab was comparable to that observed in subjects with psoriasis. Following multiple subcutaneous doses of STELARA®, the steady-state serum concentrations of ustekinumab were achieved by Week 28. The mean (±SD) steady-state trough serum concentration ranged from 0.31 ± 0.33 mcg/mL (45 mg) to 0.64 ± 0.64 mcg/mL (90 mg). There was no apparent accumulation in serum ustekinumab concentration over time when given subcutaneously every 12 weeks.
- Distribution
- Following subcutaneous administration of 45 mg (N=18) and 90 mg (N=21) of ustekinumab to subjects with psoriasis, the mean (±SD) apparent volume of distribution during the terminal phase (Vz/F) was 161 ± 65 mL/kg and 179 ± 85 mL/kg, respectively. The mean (±SD) volume of distribution during the terminal phase (Vz) following a single intravenous administration to subjects with psoriasis ranged from 56.1 ± 6.5 to 82.1 ± 23.6 mL/kg.
- Metabolism
- The metabolic pathway of ustekinumab has not been characterized. As a human IgG1κ monoclonal antibody ustekinumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.
- Elimination
- The mean (±SD) systemic clearance (CL) following a single intravenous administration of ustekinumab to subjects with psoriasis ranged from 1.90 ± 0.28 to 2.22 ± 0.63 mL/day/kg. The mean (±SD) half-life ranged from 14.9 ± 4.6 to 45.6 ± 80.2 days across all psoriasis studies following intravenous and subcutaneous administration.
- Weight
- When given the same dose, subjects with psoriasis or psoriatic arthritis weighing >100 kg had lower median serum ustekinumab concentrations compared with those subjects weighing ≤100 kg. The median trough serum concentrations of ustekinumab in subjects of higher weight (>100 kg) in the 90 mg group were comparable to those in subjects of lower weight (≤100 kg) in the 45 mg group.
- Hepatic and Renal Impairment
- No pharmacokinetic data are available in patients with hepatic or renal impairment.
- Elderly
- A population pharmacokinetic analysis (N=106/1937 subjects greater than or equal to 65 years old) was performed to evaluate the effect of age on the pharmacokinetics of ustekinumab. There were no apparent changes in pharmacokinetic parameters (clearance and volume of distribution) in subjects older than 65 years old.
- Drug-Drug Interactions
- The effects of IL-12 or IL-23 on the regulation of CYP450 enzymes were evaluated in an in vitro study using human hepatocytes, which showed that IL-12 and/or IL-23 at levels of 10 ng/mL did not alter human CYP450 enzyme activities (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4). However, the clinical relevance of in vitro data has not been established.
- Population pharmacokinetic data analyses indicated that the clearance of ustekinumab was not impacted by concomitant MTX, NSAIDs, and oral corticosteroids, or prior exposure to anti-TNFα agents in patients with psoriatic arthritis.
## Nonclinical Toxicology
- Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of STELARA®. Published literature showed that administration of murine IL-12 caused an anti-tumor effect in mice that contained transplanted tumors and IL-12/IL-23p40 knockout mice or mice treated with anti-IL-12/IL-23p40 antibody had decreased host defense to tumors. Mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone developed UV-induced skin cancers earlier and more frequently compared to wild-type mice. The relevance of these experimental findings in mouse models for malignancy risk in humans is unknown.
- No effects on fertility were observed in male cynomolgus monkeys that were administered ustekinumab at subcutaneous doses up to 45 mg/kg twice weekly (45 times the MRHD on a mg/kg basis) prior to and during the mating period. However, fertility and pregnancy outcomes were not evaluated in mated females.
- No effects on fertility were observed in female mice that were administered an analogous IL-12/IL-23p40 antibody by subcutaneous administration at doses up to 50 mg/kg, twice weekly, prior to and during early pregnancy.
- In a 26-week toxicology study, one out of 10 monkeys subcutaneously administered 45 mg/kg ustekinumab twice weekly for 26 weeks had a bacterial infection.
# Clinical Studies
- Psoriasis
- Two multicenter, randomized, double-blind, placebo-controlled studies (Ps STUDY 1 and Ps STUDY 2) enrolled a total of 1996 subjects 18 years of age and older with plaque psoriasis who had a minimum body surface area involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ≥12, and who were candidates for phototherapy or systemic therapy. Subjects with guttate, erythrodermic, or pustular psoriasis were excluded from the studies.
- Ps STUDY 1 enrolled 766 subjects and Ps STUDY 2 enrolled 1230 subjects. The studies had the same design through Week 28. In both studies, subjects were randomized in equal proportion to placebo, 45 mg or 90 mg of STELARA®. Subjects randomized to STELARA® received 45 mg or 90 mg doses, regardless of weight, at Weeks 0, 4, and 16. Subjects randomized to receive placebo at Weeks 0 and 4 crossed over to receive STELARA® (either 45 mg or 90 mg) at Weeks 12 and 16.
- In both studies, the endpoints were the proportion of subjects who achieved at least a 75% reduction in PASI score (PASI 75) from baseline to Week 12 and treatment success (cleared or minimal) on the Physician's Global Assessment (PGA). The PGA is a 6-category scale ranging from 0 (cleared) to 5 (severe) that indicates the physician's overall assessment of psoriasis focusing on plaque thickness/induration, erythema, and scaling.
- In both studies, subjects in all treatment groups had a median baseline PASI score ranging from approximately 17 to 18. Baseline PGA score was marked or severe in 44% of subjects in Ps STUDY 1 and 40% of subjects in Ps STUDY 2. Approximately two-thirds of all subjects had received prior phototherapy, 69% had received either prior conventional systemic or biologic therapy for the treatment of psoriasis, with 56% receiving prior conventional systemic therapy and 43% receiving prior biologic therapy. A total of 28% of study subjects had a history of psoriatic arthritis.
- Clinical Response
- The results of Ps STUDY 1 and Ps STUDY 2 are presented in Table 2 below.
- Examination of age, gender, and race subgroups did not identify differences in response to STELARA® among these subgroups.
- In subjects who weighed ≤100 kg, response rates were similar with both the 45 mg and 90 mg doses; however, in subjects who weighed >100 kg, higher response rates were seen with 90 mg dosing compared with 45 mg dosing (Table 3 below).
- Subjects in Ps STUDY 1 who were PASI 75 responders at both Weeks 28 and 40 were re-randomized at Week 40 to either continued dosing of STELARA® (STELARA® at Week 40) or to withdrawal of therapy (placebo at Week 40). At Week 52, 89% (144/162) of subjects re-randomized to STELARA® treatment were PASI 75 responders compared with 63% (100/159) of subjects re-randomized to placebo (treatment withdrawal after Week 28 dose). The median time to loss of PASI 75 response among the subjects randomized to treatment withdrawal was 16 weeks.
- Psoriatic Arthritis
- The safety and efficacy of STELARA® was assessed in 927 patients (PsA STUDY 1, n=615; PsA STUDY 2, n=312), in two randomized, double-blind, placebo-controlled studies in adult patients 18 years of age and older with active PsA (≥5 swollen joints and ≥5 tender joints) despite non-steroidal anti-inflammatory (NSAID) or disease modifying antirheumatic (DMARD) therapy. Patients in these studies had a diagnosis of PsA for at least 6 months. Patients with each subtype of PsA were enrolled, including polyarticular arthritis with the absence of rheumatoid nodules (39%), spondylitis with peripheral arthritis (28%), asymmetric peripheral arthritis (21%), distal interphalangeal involvement (12%) and arthritis mutilans (0.5%). Over 70% and 40% of the patients, respectively, had enthesitis and dactylitis at baseline.
- Patients were randomized to receive treatment with STELARA® 45 mg, 90 mg, or placebo subcutaneously at Weeks 0 and 4 followed by every 12 weeks (q12w) dosing. Approximately 50% of patients continued on stable doses of MTX (≤25 mg/week). The primary endpoint was the percentage of patients achieving ACR 20 response at Week 24.
- In PsA STUDY 1 and PsA STUDY 2, 80% and 86% of the patients, respectively, had been previously treated with DMARDs. In PsA STUDY 1, previous treatment with anti-tumor necrosis factor (TNF)-α agent was not allowed. In PsA STUDY 2, 58% (n=180) of the patients had been previously treated with an anti-TNFα agent, of whom over 70% had discontinued their anti-TNFα treatment for lack of efficacy or intolerance at any time.
- Clinical Response
- In both studies, a greater proportion of patients achieved ACR 20, ACR 50 and PASI 75 response in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24 (see Table 4). ACR 70 responses were also higher in the STELARA® 45 mg and 90 mg groups, although the difference was only numerical (p=NS) in Study 2. Responses were similar in patients regardless of prior TNFα exposure.
- The percent of patients achieving ACR 20 responses by visit is shown in Figure 1.
- Figure 1: Percent of patients achieving ACR 20 response through Week 24
- The results of the components of the ACR response criteria are shown in Table 5.
- An improvement in enthesitis and dactylitis scores was observed in each STELARA® group compared with placebo at Week 24.
- Physical Function
- STELARA® treated patients showed improvement in physical function compared to patients treated with placebo as assessed by HAQ-DI at Week 24. In both studies, the proportion of HAQ-DI responders (≥0.3 improvement in HAQ-DI score) was greater in the STELARA® 45 mg and 90 mg groups compared to placebo at Week 24.
# How Supplied
- STELARA® does not contain preservatives. STELARA® is available in single-use prefilled syringes or single-use vials containing 45 mg or 90 mg of ustekinumab. Each prefilled syringe is equipped with a needle safety guard.
- The NDC number for the 45 mg prefilled syringe is 57894-060-03.
- The NDC number for the 90 mg prefilled syringe is 57894-061-03.
- The NDC number for the 45 mg vial is 57894-060-02.
- The NDC number for the 90 mg vial is 57894-061-02.
- Storage and Stability
- STELARA® vials and prefilled syringes must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF). Store STELARA® vials upright. Keep the product in the original carton to protect from light until the time of use. Do not freeze. Do not shake. STELARA® does not contain a preservative; discard any unused portion.
## Storage
There is limited information regarding Ustekinumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Instruct patients to read the Medication Guide before starting STELARA® therapy and to reread the Medication Guide each time the prescription is renewed.
- Infections
- Inform patients that STELARA® may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection.
- Malignancies
- Patients should be counseled about the risk of malignancies while receiving STELARA®.
- Allergic Reactions
- Advise patients to seek immediate medical attention if they experience any symptoms of serious allergic reactions.
- Instruction on Injection Technique
- The first self-injection should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer STELARA®, he/she should be instructed in injection techniques and their ability to inject subcutaneously should be assessed to ensure the proper administration of STELARA®.
- Patients should be instructed to inject the full amount of STELARA® according to the directions provided in the Medication Guide and Instructions for Use. The needle cover on the prefilled syringe contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
- Needles and syringes should be disposed of in a puncture-resistant container. Patients or caregivers should be instructed in the technique of proper syringe and needle disposal, and be advised not to reuse these items.
# Precautions with Alcohol
- Alcohol-Ustekinumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Stelara®[2]
# Look-Alike Drug Names
There is limited information regarding Ustekinumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ustekinumab | |
1b24111cd502f40a0b58fcd5d7fdd54ef6318206 | wikidoc | Uteroglobin | Uteroglobin
Uteroglobin, also known as secretoglobin family 1A member 1 (SCGB1A1), is a protein that in humans is encoded by the SCGB1A1 gene.
SCGB1A1 is the founding member of the secretoglobin family of small, secreted, disulfide-bridged dimeric proteins found only in mammals. This antiparallel disulfide linked homodimeric protein is multifunctional and found in various tissues in various names such as: uteroglobin (UG, UGB), uteroglobin-like antigen (UGL), blastokinin, club-cell secretory protein (CCSP), Clara-cell 16 kD protein (17 in rat/mice), club-cell-specific 10 kD protein (CC10), human protein 1, urine protein 1 (UP-1), polychlorinated biphenyl-binding protein (PCB-BP), human club cell phospholipid-binding protein (hCCPBP), secretoglobin 1A member 1 (SCGB1A1).
This protein is specifically expressed in club cells in the lungs.
# Function
The precise physiological role of uteroglobin is not yet known. Putative functions are:
- Immunomodulation
- Progesterone binding: weak in some animals, especially weak in humans. (Note: UGB is itself progesterone induced gene in the endometrium in Lagomorphs)
- Inhibits phospholipase A2 in vitro
- Binds phosphatidylcholine, phosphatidylinositol
- Binds to fibronectin: The uteroglobulin knockout mice on the inbred C57Bl6 strain develop Goodpasture's syndrome like glomerulopathy due to fibronectin binding of IgA which might potentially be prevented by uteroglobin replacement. However contrary to the animal model claims, human genetic data might suggest that the effect may be indirect
- Uteroglobin knockout mice on the inbred 129 strain appear to have healthy phenotype (no glomerulopathy development), but show physiological differences in their responses to respiratory challenges. The phenotype exhibited by these mice are; decreased bioaccumulation of biphenyls, susceptibility and increased IL-13, and IL-6 following hyperoxic challenge, and changes in the club cell morphology.
- Target of polychlorinated biphenyl (pcb) binding | Uteroglobin
Uteroglobin, also known as secretoglobin family 1A member 1 (SCGB1A1), is a protein that in humans is encoded by the SCGB1A1 gene.[1]
SCGB1A1 is the founding member of the secretoglobin family of small, secreted, disulfide-bridged dimeric proteins found only in mammals.[2] This antiparallel disulfide linked homodimeric protein is multifunctional and found in various tissues in various names such as: uteroglobin (UG, UGB), uteroglobin-like antigen (UGL), blastokinin, club-cell secretory protein (CCSP), Clara-cell 16 kD protein (17 in rat/mice), club-cell-specific 10 kD protein (CC10), human protein 1, urine protein 1 (UP-1), polychlorinated biphenyl-binding protein (PCB-BP), human club cell phospholipid-binding protein (hCCPBP), secretoglobin 1A member 1 (SCGB1A1).[3]
This protein is specifically expressed in club cells in the lungs.[4]
# Function
The precise physiological role of uteroglobin is not yet known. Putative functions are:
- Immunomodulation
- Progesterone binding: weak in some animals, especially weak in humans. (Note: UGB is itself progesterone induced gene in the endometrium in Lagomorphs)
- Inhibits phospholipase A2 in vitro
- Binds phosphatidylcholine, phosphatidylinositol
- Binds to fibronectin: The uteroglobulin knockout mice on the inbred C57Bl6 strain develop Goodpasture's syndrome like glomerulopathy due to fibronectin binding of IgA which might potentially be prevented by uteroglobin replacement. However contrary to the animal model claims, human genetic data might suggest that the effect may be indirect[5]
- Uteroglobin knockout mice on the inbred 129 strain appear to have healthy phenotype (no glomerulopathy development), but show physiological differences in their responses to respiratory challenges. The phenotype exhibited by these mice are; decreased bioaccumulation of biphenyls, susceptibility and increased IL-13, and IL-6 following hyperoxic challenge, and changes in the club cell morphology. [6]
- Target of polychlorinated biphenyl (pcb) binding | https://www.wikidoc.org/index.php/Uteroglobin | |
510179e74e308724bbe23f06825786da4f2d60f0 | wikidoc | VE-cadherin | VE-cadherin
Cadherin 5, type 2 or VE-cadherin (vascular endothelial cadherin) also known as CD144 (Cluster of Differentiation 144), is a type of cadherin. It is encoded by the human gene CDH5.
# Function
VE-cadherin is a classical cadherin from the cadherin superfamily and the gene is located in a six-cadherin cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. The encoded protein is a calcium-dependent cell–cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Functioning as a classic cadherin by imparting to cells the ability to adhere in a homophilic manner, the protein may play an important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions.
Integrity of intercellular junctions is a major determinant of permeability of the endothelium, and the VE-cadherin-based adherens junction is thought to be particularly important. VE-cadherin is known to be required for maintaining a restrictive endothelial barrier – early studies using blocking antibodies to VE-cadherin increased monolayer permeability in cultured cells and resulted in interstitial edema and hemorrhage in vivo. A recent study has shown that A20 (which is a dual-ubiquitin editing enzyme) is essential for stability and expression of VE-cadherin. Deubiquitinase function of A20 was shown to remove ubiquitin chains from VE-cadherin, thereby prevented loss of VE-cadherin expression at the endothelial adherens junctions.
VE-cadherin is indispensable for proper vascular development – there have been two transgenic mouse models of VE-cadherin deficiency, both embryonic lethal due to vascular defects. Further studies using one of these models revealed that although vasculogenesis occurred, nascent vessels collapsed or disassembled in the absence of VE-cadherin. Therefore, it was concluded that VE-cadherin serves the purpose of maintaining newly formed vessels.
# Interactions
VE-cadherin has been shown to interact with:
- Beta-catenin
- Plakoglobin
- PTPRB
- Catenin (cadherin-associated protein), alpha 1
- CTNND1
- PTPmu (PTPRM)
- PTPrho (PTPRT)
# As a biomarker
VE-Cadherin may serve as a biomarker for radiation exposure. | VE-cadherin
Cadherin 5, type 2 or VE-cadherin (vascular endothelial cadherin) also known as CD144 (Cluster of Differentiation 144), is a type of cadherin. It is encoded by the human gene CDH5.[1]
# Function
VE-cadherin is a classical cadherin from the cadherin superfamily and the gene is located in a six-cadherin cluster in a region on the long arm of chromosome 16 that is involved in loss of heterozygosity events in breast and prostate cancer. The encoded protein is a calcium-dependent cell–cell adhesion glycoprotein composed of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Functioning as a classic cadherin by imparting to cells the ability to adhere in a homophilic manner, the protein may play an important role in endothelial cell biology through control of the cohesion and organization of the intercellular junctions.[2]
Integrity of intercellular junctions is a major determinant of permeability of the endothelium, and the VE-cadherin-based adherens junction is thought to be particularly important. VE-cadherin is known to be required for maintaining a restrictive endothelial barrier – early studies using blocking antibodies to VE-cadherin increased monolayer permeability in cultured cells[3] and resulted in interstitial edema and hemorrhage in vivo.[4] A recent study has shown that A20 (which is a dual-ubiquitin editing enzyme) is essential for stability and expression of VE-cadherin. Deubiquitinase function of A20 was shown to remove ubiquitin chains from VE-cadherin, thereby prevented loss of VE-cadherin expression at the endothelial adherens junctions. [5]
VE-cadherin is indispensable for proper vascular development – there have been two transgenic mouse models of VE-cadherin deficiency, both embryonic lethal due to vascular defects.[6][7] Further studies using one of these models revealed that although vasculogenesis occurred, nascent vessels collapsed or disassembled in the absence of VE-cadherin.[8] Therefore, it was concluded that VE-cadherin serves the purpose of maintaining newly formed vessels.
# Interactions
VE-cadherin has been shown to interact with:
- Beta-catenin[9][10]
- Plakoglobin[9][10]
- PTPRB[11]
- Catenin (cadherin-associated protein), alpha 1[9][10]
- CTNND1[12][13]
- PTPmu (PTPRM)[14]
- PTPrho (PTPRT)[15]
# As a biomarker
VE-Cadherin may serve as a biomarker for radiation exposure.[16] | https://www.wikidoc.org/index.php/VE-cadherin | |
423cd772abb6526cb2ea65a560e2e648732a9563 | wikidoc | VS ribozyme | VS ribozyme
The Varkud satellite (VS) ribozyme carries out the cleavage of a phosphodiester bond .
# Structure
The VS ribozyme is composed of 5 helices that form an H shape (helices II to VI). The first helix (I) contains the substrate cleavage site in the stem loop.
# Species Distribution
The VS ribozyme has only been found in DNA of Neurospora mitochondria. | VS ribozyme
The Varkud satellite (VS) ribozyme carries out the cleavage of a phosphodiester bond [1].
## Structure
The VS ribozyme is composed of 5 helices that form an H shape (helices II to VI). The first helix (I) contains the substrate cleavage site in the stem loop.
## Species Distribution
The VS ribozyme has only been found in DNA of Neurospora mitochondria. | https://www.wikidoc.org/index.php/VS_ribozyme | |
46a91644f2dcdb1e6b6576bbd8d968c2c442d6b7 | wikidoc | Vaginectomy | Vaginectomy
# Overview
Vaginectomy is a medical procedure to remove all or part of the vagina. It is usually used as a treatment for vaginal cancer. Vaginectomy is also used as part of some types of female-to-male sex reassignment surgery.
# Cancer
Vaginectomy can be divided into two kinds of operations.
An operation under which the whole vagina is removed is called a radical vaginectomy. If only the upper part of the vagina is removed then the operation is called a partial vaginectomy. The doctor will decide depending the severity of the case and the affected areas.
Usually after a radical vaginoplasty a plastic surgeon will perform a vaginal reconstruction, using skin and muscle from other body parts, for aesthetic reasons. | Vaginectomy
# Overview
Vaginectomy is a medical procedure to remove all or part of the vagina. It is usually used as a treatment for vaginal cancer. Vaginectomy is also used as part of some types of female-to-male sex reassignment surgery.
# Cancer
Vaginectomy can be divided into two kinds of operations.
An operation under which the whole vagina is removed is called a radical vaginectomy. If only the upper part of the vagina is removed then the operation is called a partial vaginectomy. The doctor will decide depending the severity of the case and the affected areas.
Usually after a radical vaginoplasty a plastic surgeon will perform a vaginal reconstruction, using skin and muscle from other body parts, for aesthetic reasons.
# External links
Vaginoplasty Images
# Sources
Cancer Help
Template:Urogenital surgical and other procedures
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Vaginectomy | |
9cb10aa019915cf4acb91a105e558f8106339ec6 | wikidoc | Valbenazine | Valbenazine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that is FDA approved for the treatment of adults with tardive dyskinesia. Common adverse reactions include somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Valbenazine is indicated for the treatment of adults with tardive dyskinesia.
- The initial dose for valbenazine is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.
- Administer valbenazine orally with or without food.
- The recommended dose for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is valbenazine 40 mg once daily.
- Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers.
Coadministration with Strong CYP3A4 Inducers
- Concomitant use of strong CYP3A4 inducers with valbenazine is not recommended.
Coadministration with Strong CYP3A4 Inhibitors
- Reduce valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP3A4 inhibitor.
- Consider reducing valbenazine dose based on tolerability when valbenazine is coadministered with a strong CYP2D6 inhibitor.
- Valbenazine capsules are available in the following strengths:
- 40 mg capsules with a white opaque body and purple cap, printed with ‘VBZ’ and ‘40’ in black ink.
- 80 mg capsules with a purple opaque body and cap, printed with ‘VBZ’ and ‘80’ in black ink.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Valbenazine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Valbenazine can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by valbenazine.
- Valbenazine may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. In patients taking a strong CYP2D6 or CYP3A4 inhibitor, or who are CYP2D6 poor metabolizers, valbenazine concentrations may be higher and QT prolongation clinically significant. For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. For patients taking a strong CYP3A4 inhibitor, reduce the dose of valbenazine to 40 mg once daily. Valbenazine should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of valbenazine was evaluated in 3 placebo-controlled studies, each 6 weeks in duration (fixed dose, dose escalation, dose reduction), including 445 patients. Patients were 26 to 84 years of age with moderate to severe tardive dyskinesia and had concurrent diagnoses of mood disorder (27%) or schizophrenia/ schizoaffective disorder (72%). The mean age was 56 years. Patients were 57% Caucasian, 39% African-American, and 4% other. With respect to ethnicity, 28% were Hispanic or Latino. All subjects continued previous stable regimens of antipsychotics; 85% and 27% of subjects, respectively, were taking atypical and typical antipsychotic medications at study entry.
Adverse Reactions Leading to Discontinuation of Treatment
- A total of 3% of valbenazine treated patients and 2% of placebo-treated patients discontinued because of adverse reactions.
Common Adverse Reactions
- Adverse reactions that occurred in the 3 placebo-controlled studies at an incidence of ≥2% and greater than placebo are presented in Table 1.
Other Adverse Reactions Observed During the Premarketing Evaluation of Valbenazine
- Other adverse reactions of ≥1% incidence and greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.
- Endocrine Disorders: blood glucose increased.
- General Disorders: weight increased.
- Infectious Disorders: respiratory infections.
- Neurologic Disorders: drooling, dyskinesia, extrapyramidal symptoms (non-akathisia).
- Psychiatric Disorders: anxiety, insomnia.
- During controlled trials, there was a dose-related increase in prolactin. Additionally, there was a dose-related increase in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis.
## Postmarketing Experience
There is limited information regarding Valbenazine Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs Having Clinically Important Interactions with Valbenazine
- Drugs Having No Clinically Important Interactions with Valbenazine
- Dosage adjustment for valbenazine is not necessary when used in combination with substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 based on in vitro study results.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m2. Advise a pregnant woman of the potential risk to a fetus.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively.
- Valbenazine was administered orally to pregnant rats during the period of organogenesis at 1, 5, and 15 mg/kg/day, which are approximately 0.1, 0.6, and 2 times the MRHD of 80 mg/day based on mg/m2 body surface area. Valbenazine produced a significant decrease in maternal body weight gain at 0.6 and 2 times the MRHD of 80 mg/day based on mg/m2. No adverse embryo fetal effects were produced when valbenazine was administered at doses up to 2 times the MRHD of 80 mg/day based on mg/m2.
- Valbenazine was administered orally to pregnant rabbits during the period of organogenesis at 20, 50, and 100 mg/kg/day, which are approximately 5, 12, and 24 times the MRHD of 80 mg/day based on mg/m2. No malformations were observed at doses up to 24 times the MRHD of 80 mg/day based on mg/m2. However, valbenazine produced a delay in fetal development (decreased fetal weights and delayed ossification) at 24 times the MRHD of 80 mg/day based on mg/m2, likely secondary to maternal toxicity (decreased food intake and loss in body weight).
- Valbenazine was administered orally to pregnant rats during the period of organogenesis through lactation (day 7 of gestation through day 20 postpartum) at 1, 3, and 10 mg/kg/day, which are approximately 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine produced an increase in the incidence of stillbirths and postnatal pup mortality at 0.4 and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine did not affect neurobehavioral function including learning and memory and had no effect on sexual maturation at doses <1 times the MRHD of 80 mg/day based on mg/m2 (because of death in the majority of the high dose group (1.2 times the MRHD), these parameters were not assessed in this group).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valbenazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Valbenazine during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of valbenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Valbenazine and its metabolites have been detected in rat milk at concentrations higher than in plasma following oral administration of valbenazine at doses 0.1 to 1.2 times the MRHD based on mg/m2. Based on animal findings of increased perinatal mortality in exposed fetuses and pups, advise a woman not to breastfeed during treatment with valbenazine and for 5 days after the final dose.
### Pediatric Use
- Safety and effectiveness of valbenazine have not been established in pediatric patients.
### Geriatic Use
- No dose adjustment is required for elderly patients. In 3 randomized, placebo-controlled studies of valbenazine, 16% were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients.
### Gender
There is no FDA guidance on the use of Valbenazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Valbenazine with respect to specific racial populations.
### Renal Impairment
- Dosage adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance 30 to 90 mL/min). Valbenazine does not undergo primary renal clearance. Valbenazine is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).
### Hepatic Impairment
- Dosage reduction of valbenazine is recommended for patients with moderate or severe hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valbenazine in women of reproductive potentials and males.
### Immunocompromised Patients
- Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers. Increased exposure (Cmax and AUC) to valbenazine’s active metabolite is anticipated in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.
# Administration and Monitoring
### Administration
- The initial dose for valbenazine is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.
- Administer valbenazine orally with or without food.
### Monitoring
- Decrease in severity of tardive dyskinesia symptoms is indicative of efficacy.
- QT interval: Patients at increased risk of prolonged QT interval, prior to increasing dose.
# IV Compatibility
There is limited information regarding the compatibility of Valbenazine and IV administrations.
# Overdosage
- The pre-marketing clinical trials involving valbenazine in approximately 850 subjects do not provide information regarding symptoms with overdose.
- No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).
# Pharmacology
## Mechanism of Action
- The mechanism of action of valbenazine in the treatment of tardive dyskinesia is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.
## Structure
## Pharmacodynamics
- Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite -α-dihydrotetrabenazine (-α-HTBZ).
- -α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and -α-HTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors.
- Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6 poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean QT prolongation of 11.7 msec (14.7 msec upper bound of double-sided 90% CI) as compared to otherwise healthy volunteers given valbenazine, who had a mean QT prolongation of 6.7 msec (8.4 msec).
## Pharmacokinetics
- Valbenazine and its active metabolite (-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose).
- Following oral administration, the time to reach maximum valbenazine plasma concentration (tmax) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. -α-HTBZ gradually forms and reaches Cmax 4 to 8 hours after administration of valbenazine.
- Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. -α-HTBZ Cmax and AUC are unaffected.
- The plasma protein binding of valbenazine and -α-HTBZ are greater than 99% and approximately 64%, respectively. The mean steady state volume of distribution of valbenazine is 92 L.
- Nonclinical data in Long-Evans rats show that valbenazine can bind to melanin-containing structures of the eye such as the uveal tract. The relevance of this observation to clinical use of valbenazine is unknown.
- Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr. Valbenazine and -α-HTBZ have half-lives of 15 to 22 hours.
Metabolism
- Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite (-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. -α-HTBZ appears to be further metabolized in part by CYP2D6.
- The results of in vitro studies suggest that valbenazine and -α-HTBZ are unlikely to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5, or induce CYP1A2, CYP2B6 or CYP3A4/5 at clinically relevant concentrations.
- The results of in vitro studies suggest that valbenazine and -α-HTBZ are unlikely to inhibit the transporters (BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3) at clinically relevant concentrations.
Excretion
- Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or -α-HTBZ in either urine or feces.
- Exposures of valbenazine in patients with hepatic impairment are summarized in Figure 1.
- The effects of ketoconazole and rifampin on the exposure of valbenazine are summarized in Figure 2.
- The effects of valbenazine on the exposure of other coadministered drugs are summarized in Figure 3.
## Nonclinical Toxicology
- Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m2.
- Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30 and 75 mg/kg/day, which are 0.6, 1.9 and 4.6 times the MRHD of 80 mg/day based on mg/m2.
- Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.
- In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2, respectively. Valbenazine delayed mating in both sexes, which led to lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions and post-implantation loss) at any dose.
# Clinical Studies
- A randomized, double-blind, placebo-controlled trial of valbenazine was conducted in patients with moderate to severe tardive dyskinesia as determined by clinical observation. Patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder. Individuals at significant risk for suicidal or violent behavior and individuals with unstable psychiatric symptoms were excluded.
- The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=no dyskinesia; 1=low amplitude, present during some but not most of the exam; 2=low amplitude and present during most of the exam (or moderate amplitude and present during some of the exam); 3=moderate amplitude and present during most of exam; or 4=maximal amplitude and present during most of exam. The AIMS dyskinesia total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement. The AIMS was scored by central raters who interpreted the videos blinded to subject identification, treatment assignment, and visit number.
- The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. The change from baseline for two fixed doses of valbenazine (40 mg or 80 mg) was compared to placebo. At the end of Week 6, subjects initially assigned to placebo were re-randomized to receive valbenazine 40 mg or 80 mg. Subjects originally randomized to valbenazine continued valbenazine at their randomized dose. Follow-up was continued through Week 48 on the assigned drug, followed by a 4-week period off-drug (subjects were not blind to withdrawal).
- A total of 234 subjects were enrolled, with 29 (12%) discontinuing prior to completion of the placebo-controlled period. Mean age was 56 (range 26 to 84). Patients were 54% male and 46% female. Patients were 57% Caucasian, 38% African-American, and 5% other. Concurrent diagnoses included schizophrenia/schizoaffective disorder (66%) and mood disorder (34%). With respect to concurrent antipsychotic use, 70% of subjects were receiving atypical antipsychotics, 14% were receiving typical or combination antipsychotics, and 16% were not receiving antipsychotics.
- Results are presented in Table 3, with the distribution of responses shown in Figure 4. The change from baseline in the AIMS total dyskinesia score in the 80 mg valbenazine group was statistically significantly different from the change in the placebo group. Subgroup analyses by gender, age, racial subgroup, underlying psychiatric diagnostic category, and concomitant antipsychotic medication did not suggest any clear evidence of differential responsiveness.
- The mean changes in the AIMS dyskinesia total score by visit are shown in Figure 5. Among subjects remaining in the study at the end of the 48-week treatment (N=123 ), following discontinuation of valbenazine, the mean AIMS dyskinesia total score appeared to return toward baseline (there was no formal hypothesis testing for the change following discontinuation).
# How Supplied
- Valbenazine capsules are available as:
- 40 mg Capsule: White opaque body with a purple cap, printed with ‘VBZ’ and ‘40’ in black ink.
- Bottle of 30: NDC 70370-1040-1
- Bottle of 90: NDC 70370-1040-2
- 80 mg Capsule: Purple opaque body and cap, printed with ‘VBZ’ and ‘80’ in black ink.
- Bottle of 30: NDC 70370-1080-1
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Inform patients that valbenazine may cause somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to valbenazine, they should be careful or avoid doing activities that require them to be alert, such as driving a car or operating machinery.
- Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations. Advise patients to inform physicians that they are taking valbenazine before any new drug is taken.
- Advise a pregnant patient of the potential risk to a fetus.
- Advise a woman not to breastfeed during treatment with valbenazine and for 5 days after the final dose.
# Precautions with Alcohol
Alcohol-Valbenazine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Ingrezza
# Look-Alike Drug Names
There is limited information regarding Valbenazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Valbenazine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Valbenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor that is FDA approved for the treatment of adults with tardive dyskinesia. Common adverse reactions include somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Valbenazine is indicated for the treatment of adults with tardive dyskinesia.
- The initial dose for valbenazine is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.
- Administer valbenazine orally with or without food.
- The recommended dose for patients with moderate or severe hepatic impairment (Child-Pugh score 7 to 15) is valbenazine 40 mg once daily.
- Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers.
Coadministration with Strong CYP3A4 Inducers
- Concomitant use of strong CYP3A4 inducers with valbenazine is not recommended.
Coadministration with Strong CYP3A4 Inhibitors
- Reduce valbenazine dose to 40 mg once daily when valbenazine is coadministered with a strong CYP3A4 inhibitor.
- Consider reducing valbenazine dose based on tolerability when valbenazine is coadministered with a strong CYP2D6 inhibitor.
- Valbenazine capsules are available in the following strengths:
- 40 mg capsules with a white opaque body and purple cap, printed with ‘VBZ’ and ‘40’ in black ink.
- 80 mg capsules with a purple opaque body and cap, printed with ‘VBZ’ and ‘80’ in black ink.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Valbenazine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding valbenazine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- None.
# Warnings
- Valbenazine can cause somnolence. Patients should not perform activities requiring mental alertness such as operating a motor vehicle or operating hazardous machinery until they know how they will be affected by valbenazine.
- Valbenazine may prolong the QT interval, although the degree of QT prolongation is not clinically significant at concentrations expected with recommended dosing. In patients taking a strong CYP2D6 or CYP3A4 inhibitor, or who are CYP2D6 poor metabolizers, valbenazine concentrations may be higher and QT prolongation clinically significant. For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary. For patients taking a strong CYP3A4 inhibitor, reduce the dose of valbenazine to 40 mg once daily. Valbenazine should be avoided in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. For patients at increased risk of a prolonged QT interval, assess the QT interval before increasing the dosage.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety of valbenazine was evaluated in 3 placebo-controlled studies, each 6 weeks in duration (fixed dose, dose escalation, dose reduction), including 445 patients. Patients were 26 to 84 years of age with moderate to severe tardive dyskinesia and had concurrent diagnoses of mood disorder (27%) or schizophrenia/ schizoaffective disorder (72%). The mean age was 56 years. Patients were 57% Caucasian, 39% African-American, and 4% other. With respect to ethnicity, 28% were Hispanic or Latino. All subjects continued previous stable regimens of antipsychotics; 85% and 27% of subjects, respectively, were taking atypical and typical antipsychotic medications at study entry.
Adverse Reactions Leading to Discontinuation of Treatment
- A total of 3% of valbenazine treated patients and 2% of placebo-treated patients discontinued because of adverse reactions.
Common Adverse Reactions
- Adverse reactions that occurred in the 3 placebo-controlled studies at an incidence of ≥2% and greater than placebo are presented in Table 1.
Other Adverse Reactions Observed During the Premarketing Evaluation of Valbenazine
- Other adverse reactions of ≥1% incidence and greater than placebo are shown below. The following list does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.
- Endocrine Disorders: blood glucose increased.
- General Disorders: weight increased.
- Infectious Disorders: respiratory infections.
- Neurologic Disorders: drooling, dyskinesia, extrapyramidal symptoms (non-akathisia).
- Psychiatric Disorders: anxiety, insomnia.
- During controlled trials, there was a dose-related increase in prolactin. Additionally, there was a dose-related increase in alkaline phosphatase and bilirubin, suggesting a potential risk for cholestasis.
## Postmarketing Experience
There is limited information regarding Valbenazine Postmarketing Experience in the drug label.
# Drug Interactions
- Drugs Having Clinically Important Interactions with Valbenazine
- Drugs Having No Clinically Important Interactions with Valbenazine
- Dosage adjustment for valbenazine is not necessary when used in combination with substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 based on in vitro study results.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- The limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m2. Advise a pregnant woman of the potential risk to a fetus.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risk of major birth defects and miscarriage in the U.S. general population is 2-4% and 15-20% of clinically recognized pregnancies, respectively.
- Valbenazine was administered orally to pregnant rats during the period of organogenesis at 1, 5, and 15 mg/kg/day, which are approximately 0.1, 0.6, and 2 times the MRHD of 80 mg/day based on mg/m2 body surface area. Valbenazine produced a significant decrease in maternal body weight gain at 0.6 and 2 times the MRHD of 80 mg/day based on mg/m2. No adverse embryo fetal effects were produced when valbenazine was administered at doses up to 2 times the MRHD of 80 mg/day based on mg/m2.
- Valbenazine was administered orally to pregnant rabbits during the period of organogenesis at 20, 50, and 100 mg/kg/day, which are approximately 5, 12, and 24 times the MRHD of 80 mg/day based on mg/m2. No malformations were observed at doses up to 24 times the MRHD of 80 mg/day based on mg/m2. However, valbenazine produced a delay in fetal development (decreased fetal weights and delayed ossification) at 24 times the MRHD of 80 mg/day based on mg/m2, likely secondary to maternal toxicity (decreased food intake and loss in body weight).
- Valbenazine was administered orally to pregnant rats during the period of organogenesis through lactation (day 7 of gestation through day 20 postpartum) at 1, 3, and 10 mg/kg/day, which are approximately 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine produced an increase in the incidence of stillbirths and postnatal pup mortality at 0.4 and 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine did not affect neurobehavioral function including learning and memory and had no effect on sexual maturation at doses <1 times the MRHD of 80 mg/day based on mg/m2 (because of death in the majority of the high dose group (1.2 times the MRHD), these parameters were not assessed in this group).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valbenazine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Valbenazine during labor and delivery.
### Nursing Mothers
- There is no information regarding the presence of valbenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Valbenazine and its metabolites have been detected in rat milk at concentrations higher than in plasma following oral administration of valbenazine at doses 0.1 to 1.2 times the MRHD based on mg/m2. Based on animal findings of increased perinatal mortality in exposed fetuses and pups, advise a woman not to breastfeed during treatment with valbenazine and for 5 days after the final dose.
### Pediatric Use
- Safety and effectiveness of valbenazine have not been established in pediatric patients.
### Geriatic Use
- No dose adjustment is required for elderly patients. In 3 randomized, placebo-controlled studies of valbenazine, 16% were 65 years and older. The safety and effectiveness were similar in patients older than 65 years compared to younger patients.
### Gender
There is no FDA guidance on the use of Valbenazine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Valbenazine with respect to specific racial populations.
### Renal Impairment
- Dosage adjustment is not necessary for patients with mild to moderate renal impairment (creatinine clearance 30 to 90 mL/min). Valbenazine does not undergo primary renal clearance. Valbenazine is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min).
### Hepatic Impairment
- Dosage reduction of valbenazine is recommended for patients with moderate or severe hepatic impairment. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valbenazine in women of reproductive potentials and males.
### Immunocompromised Patients
- Consider reducing valbenazine dose based on tolerability for known CYP2D6 poor metabolizers. Increased exposure (Cmax and AUC) to valbenazine’s active metabolite is anticipated in CYP2D6 poor metabolizers. Increased exposure of active metabolite may increase the risk of exposure-related adverse reactions.
# Administration and Monitoring
### Administration
- The initial dose for valbenazine is 40 mg once daily. After one week, increase the dose to the recommended dose of 80 mg once daily. Continuation of 40 mg once daily may be considered for some patients.
- Administer valbenazine orally with or without food.
### Monitoring
- Decrease in severity of tardive dyskinesia symptoms is indicative of efficacy.
- QT interval: Patients at increased risk of prolonged QT interval, prior to increasing dose.
# IV Compatibility
There is limited information regarding the compatibility of Valbenazine and IV administrations.
# Overdosage
- The pre-marketing clinical trials involving valbenazine in approximately 850 subjects do not provide information regarding symptoms with overdose.
- No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center (1-800-222-1222 or www.poison.org).
# Pharmacology
## Mechanism of Action
- The mechanism of action of valbenazine in the treatment of tardive dyskinesia is unknown, but is thought to be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release.
## Structure
## Pharmacodynamics
- Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ).
- [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-α-HTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors.
- Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6 poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean QT prolongation of 11.7 msec (14.7 msec upper bound of double-sided 90% CI) as compared to otherwise healthy volunteers given valbenazine, who had a mean QT prolongation of 6.7 msec (8.4 msec).
## Pharmacokinetics
- Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose).
- Following oral administration, the time to reach maximum valbenazine plasma concentration (tmax) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches Cmax 4 to 8 hours after administration of valbenazine.
- Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected.
- The plasma protein binding of valbenazine and [+]-α-HTBZ are greater than 99% and approximately 64%, respectively. The mean steady state volume of distribution of valbenazine is 92 L.
- Nonclinical data in Long-Evans rats show that valbenazine can bind to melanin-containing structures of the eye such as the uveal tract. The relevance of this observation to clinical use of valbenazine is unknown.
- Valbenazine has a mean total plasma systemic clearance value of 7.2 L/hr. Valbenazine and [+]-α-HTBZ have half-lives of 15 to 22 hours.
Metabolism
- Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6.
- The results of in vitro studies suggest that valbenazine and [+]-α-HTBZ are unlikely to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 or CYP3A4/5, or induce CYP1A2, CYP2B6 or CYP3A4/5 at clinically relevant concentrations.
- The results of in vitro studies suggest that valbenazine and [+]-α-HTBZ are unlikely to inhibit the transporters (BCRP, OAT1, OAT3, OCT2, OATP1B1, or OATP1B3) at clinically relevant concentrations.
Excretion
- Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or feces.
- Exposures of valbenazine in patients with hepatic impairment are summarized in Figure 1.
- The effects of ketoconazole and rifampin on the exposure of valbenazine are summarized in Figure 2.
- The effects of valbenazine on the exposure of other coadministered drugs are summarized in Figure 3.
## Nonclinical Toxicology
- Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m2.
- Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30 and 75 mg/kg/day, which are 0.6, 1.9 and 4.6 times the MRHD of 80 mg/day based on mg/m2.
- Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay.
- In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m2, respectively. Valbenazine delayed mating in both sexes, which led to lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m2. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions and post-implantation loss) at any dose.
# Clinical Studies
- A randomized, double-blind, placebo-controlled trial of valbenazine was conducted in patients with moderate to severe tardive dyskinesia as determined by clinical observation. Patients had underlying schizophrenia, schizoaffective disorder, or a mood disorder. Individuals at significant risk for suicidal or violent behavior and individuals with unstable psychiatric symptoms were excluded.
- The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=no dyskinesia; 1=low amplitude, present during some but not most of the exam; 2=low amplitude and present during most of the exam (or moderate amplitude and present during some of the exam); 3=moderate amplitude and present during most of exam; or 4=maximal amplitude and present during most of exam. The AIMS dyskinesia total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement. The AIMS was scored by central raters who interpreted the videos blinded to subject identification, treatment assignment, and visit number.
- The primary efficacy endpoint was the mean change from baseline in the AIMS dyskinesia total score at the end of Week 6. The change from baseline for two fixed doses of valbenazine (40 mg or 80 mg) was compared to placebo. At the end of Week 6, subjects initially assigned to placebo were re-randomized to receive valbenazine 40 mg or 80 mg. Subjects originally randomized to valbenazine continued valbenazine at their randomized dose. Follow-up was continued through Week 48 on the assigned drug, followed by a 4-week period off-drug (subjects were not blind to withdrawal).
- A total of 234 subjects were enrolled, with 29 (12%) discontinuing prior to completion of the placebo-controlled period. Mean age was 56 (range 26 to 84). Patients were 54% male and 46% female. Patients were 57% Caucasian, 38% African-American, and 5% other. Concurrent diagnoses included schizophrenia/schizoaffective disorder (66%) and mood disorder (34%). With respect to concurrent antipsychotic use, 70% of subjects were receiving atypical antipsychotics, 14% were receiving typical or combination antipsychotics, and 16% were not receiving antipsychotics.
- Results are presented in Table 3, with the distribution of responses shown in Figure 4. The change from baseline in the AIMS total dyskinesia score in the 80 mg valbenazine group was statistically significantly different from the change in the placebo group. Subgroup analyses by gender, age, racial subgroup, underlying psychiatric diagnostic category, and concomitant antipsychotic medication did not suggest any clear evidence of differential responsiveness.
- The mean changes in the AIMS dyskinesia total score by visit are shown in Figure 5. Among subjects remaining in the study at the end of the 48-week treatment (N=123 [52.6%]), following discontinuation of valbenazine, the mean AIMS dyskinesia total score appeared to return toward baseline (there was no formal hypothesis testing for the change following discontinuation).
# How Supplied
- Valbenazine capsules are available as:
- 40 mg Capsule: White opaque body with a purple cap, printed with ‘VBZ’ and ‘40’ in black ink.
- Bottle of 30: NDC 70370-1040-1
- Bottle of 90: NDC 70370-1040-2
- 80 mg Capsule: Purple opaque body and cap, printed with ‘VBZ’ and ‘80’ in black ink.
- Bottle of 30: NDC 70370-1080-1
## Storage
- Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling.
- Inform patients that valbenazine may cause somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Advise patients that until they learn how they respond to valbenazine, they should be careful or avoid doing activities that require them to be alert, such as driving a car or operating machinery.
- Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations. Advise patients to inform physicians that they are taking valbenazine before any new drug is taken.
- Advise a pregnant patient of the potential risk to a fetus.
- Advise a woman not to breastfeed during treatment with valbenazine and for 5 days after the final dose.
# Precautions with Alcohol
Alcohol-Valbenazine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Ingrezza
# Look-Alike Drug Names
There is limited information regarding Valbenazine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Valbenazine | |
d000e4293d0c8dec15d7ead62485479c571ab90f | wikidoc | Valinomycin | Valinomycin
Valinomycin is a dodecadepsipeptide, that is, it is made of twelve alternating amino acids and esters to form a macrocyclic molecule.
Valinomycin is obtained from the cells of several Streptomyces strains, one of them Str. Tsusimaensis.
It is a member of the group of natural neutral ionophores because it doesn't have a residual charge. It consists of enantiomeres D-Valine and L-Valine, D-Hydroxyvaleric acid and L-Lactic acid. Structures are alternated bound via amide and ester bridges. Valinomycin is highly selective for potassium ions over sodium ions within the cell membrane. It functions as a potassium-specific transporter and facilitates the movement of potassium ions through lipid membranes "down" an electrochemical potential gradient. The stability constant K for the potassium-valinomycin complex is 106 and for the sodium-valinomycin complex only 10. This difference is important for maintaining the selectivity of valinomycin for the transport of potassium ions (and not sodium ions) in biological systems.
# Structure
From the chemical structure it can be seen that there are some prevailing features. The 12 carbonyl groups are essential for the binding of metal ions, and also for solvatation in polar solvent. The isopropyl groups and methyl groups are responsible for solvatation in nonpolar solvents.
Along with its shape and size this molecular duality is the main reason for its binding properties. For polar solvents valinomycin will mainly expose the carbonyls to the solvent and in nonpolar solvents the iso-propyl groups are located predominantly on the exterior of the molecule. This conformation changes when valinomycin is bound to a potassium ion. The molecule is "locked" into a conformation where the exterior is made up of the isopropyl groups. It is not actually locked into configuration because the size of the molecule makes it highly flexible, but the potassium gives some degree of coordination to the macromolecule.
# Application
Valinomycin acts as ion-exchange agent in Potassium selective electrode. | Valinomycin
Template:Chembox new
Valinomycin is a dodecadepsipeptide, that is, it is made of twelve alternating amino acids and esters to form a macrocyclic molecule.
Valinomycin is obtained from the cells of several Streptomyces strains, one of them Str. Tsusimaensis.
It is a member of the group of natural neutral ionophores because it doesn't have a residual charge. It consists of enantiomeres D-Valine and L-Valine, D-Hydroxyvaleric acid and L-Lactic acid. Structures are alternated bound via amide and ester bridges. Valinomycin is highly selective for potassium ions over sodium ions within the cell membrane.[1] It functions as a potassium-specific transporter and facilitates the movement of potassium ions through lipid membranes "down" an electrochemical potential gradient.[2] The stability constant K for the potassium-valinomycin complex is 106 and for the sodium-valinomycin complex only 10. This difference is important for maintaining the selectivity of valinomycin for the transport of potassium ions (and not sodium ions) in biological systems.
# Structure
From the chemical structure it can be seen that there are some prevailing features. The 12 carbonyl groups are essential for the binding of metal ions, and also for solvatation in polar solvent. The isopropyl groups and methyl groups are responsible for solvatation in nonpolar solvents.
[3] Along with its shape and size this molecular duality is the main reason for its binding properties. For polar solvents valinomycin will mainly expose the carbonyls to the solvent and in nonpolar solvents the iso-propyl groups are located predominantly on the exterior of the molecule. This conformation changes when valinomycin is bound to a potassium ion. The molecule is "locked" into a conformation where the exterior is made up of the isopropyl groups. It is not actually locked into configuration because the size of the molecule makes it highly flexible, but the potassium gives some degree of coordination to the macromolecule.
# Application
Valinomycin acts as ion-exchange agent in Potassium selective electrode.[4] | https://www.wikidoc.org/index.php/Valinomycin | |
603513b39ecf374691b794ff9d5eb837505af9ed | wikidoc | Varenicline | Varenicline
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Varenicline is a neurotransmitter agent that is FDA approved for the treatment of smoking cessation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, abnormal (e.g., vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Usual Dosage for Adults
- Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.
- The patient should set a date to stop smoking. Begin CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.
- CHANTIX should be taken after eating and with a full glass of water.
- The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:
- Patients should be treated with CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.
- Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed.
- Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
- Dosage in Special Populations
- Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated.
- Elderly and Patients with Impaired Hepatic Function: No dosage adjustment is necessary for patients with hepatic impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- DOSAGE FORMS AND STRENGTHS
- Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Varenicline in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Varenicline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Varenicline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Varenicline in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Varenicline in pediatric patients.
# Contraindications
- CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.
# Warnings
Neuropsychiatric Symptoms and Suicidality
- Serious neuropsychiatric symptoms have been reported in patients being treated with CHANTIX. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke. When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy.
- These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses. All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX, and the safety and efficacy of CHANTIX in such patients has not been established. Limited data are available from a single smoking cessation study in patients with stable schizophrenia or schizoaffective disorder.
- Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, depressed mood, changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
- The risks of CHANTIX should be weighed against the benefits of its use. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
Angioedema and Hypersensitivity Reactions
- There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.
Serious Skin Reactions
- There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using CHANTIX. As these skin reactions can be life-threatening, instruct patients to stop taking CHANTIX and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.
Cardiovascular Events
- In a placebo-controlled clinical trial of CHANTIX administered to patients with stable cardiovascular disease, with approximately 350 patients per treatment arm, all-cause and cardiovascular mortality was lower in patients treated with CHANTIX, but certain nonfatal cardiovascular events occurred more frequently in patients treated with CHANTIX than in patients treated with placebo. Table 1 below shows the incidence of deaths and of selected nonfatal serious cardiovascular events occurring more frequently in the CHANTIX arm compared to the placebo arm. These events were adjudicated by an independent blinded committee. Nonfatal serious cardiovascular events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one cardiovascular event of the same type are counted only once per row. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina.
- A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients (4190 CHANTIX, 2812 placebo), was conducted to systematically assess the cardiovascular safety of CHANTIX. The study in patients with stable cardiovascular disease described above was included in the meta-analysis. There were lower rates of all-cause mortality (CHANTIX 6 ; placebo 7 ) and cardiovascular mortality (CHANTIX 2 ; placebo 2 ) in the CHANTIX arms compared with the placebo arms in the meta-analysis.
- The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as cardiovascular death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small number of MACE occurred in the trials included in the meta-analysis, as described in Table 2. These events occurred primarily in patients with known cardiovascular disease.
- The meta-analysis showed that exposure to CHANTIX resulted in a hazard ratio for MACE of 1.95 (95% confidence interval from 0.79 to 4.82) for patients up to 30 days after treatment; this is equivalent to an estimated increase of 6.3 MACE events per 1,000 patient-years of exposure. The meta-analysis showed higher rates of CV endpoints in patients on CHANTIX relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and CV outcomes. Although these findings were not statistically significant they were consistent. Because the number of events was small overall, the power for finding a statistically significant difference in a signal of this magnitude is low.
- CHANTIX was not studied in patients with unstable cardiovascular disease or cardiovascular events occurring within two months before screening. Patients should be advised to notify a health care provider of new or worsening symptoms of cardiovascular disease. The risks of CHANTIX should be weighed against the benefits of its use in smokers with cardiovascular disease. Smoking is an independent and major risk factor for cardiovascular disease. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
Accidental Injury
- There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX. In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how CHANTIX may affect them.
Nausea
- Nausea was the most common adverse reaction reported with CHANTIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen. In patients taking CHANTIX 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
- Varenicline is not a controlled substance.
### Dependence
- Humans: Fewer than 1 out of 1000 patients reported euphoria in clinical trials with CHANTIX. At higher doses (greater than 2 mg), CHANTIX produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. Abrupt discontinuation of CHANTIX was associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction.
- In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers.
- Animals: Studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline pretreatment also reduced nicotine self-administration.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling:
- Neuropsychiatric symptoms and suicidality
- Angioedema and hypersensitivity reactions
- Accidental injury
- In the placebo-controlled studies, the most common adverse events associated with CHANTIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
- The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in studies of three months' treatment. In this group, the discontinuation rates that are higher than placebo for the most common adverse events in CHANTIX-treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo).
- Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- During the premarketing development of CHANTIX, over 4500 subjects were exposed to CHANTIX, with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants were treated for 12 weeks or less.
- The most common adverse event associated with CHANTIX treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen.
- Table 3 shows the adverse events for CHANTIX and placebo in the 12-week fixed dose studies with titration in the first week . Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).
- MedDRA High Level Group Terms (HLGT) reported in ≥ 5% of patients in the CHANTIX 1 mg twice daily dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥ 1% of CHANTIX patients (and at least 0.5% more frequent than placebo). Closely related Preferred Terms such as 'Insomnia', 'Initial insomnia', 'Middle insomnia', 'Early morning awakening' were grouped, but individual patients reporting two or more grouped events are only counted once.
- The overall pattern and frequency of adverse events during the longer-term trials was similar to those described in Table 3, though several of the most common events were reported by a greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated with CHANTIX 1 mg twice daily in a one-year study, compared to 8% of placebo-treated patients).
- Following is a list of treatment-emergent adverse events reported by patients treated with CHANTIX during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.
- Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.
- Cardiac Disorders. Infrequent: angina pectoris, arrhythmia, bradycardia, myocardial infarction, palpitations, tachycardia, ventricular extrasystoles. Rare: acute coronary syndrome, atrial fibrillation, cardiac flutter, cor pulmonale, coronary artery disease.
- Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease.
- Endocrine Disorders. Infrequent: thyroid gland disorders.
- Eye Disorders. Infrequent: conjunctivitis, dry eye, eye irritation, eye pain, vision blurred, visual disturbance. Rare: acquired night blindness, blindness transient, cataract subcapsular, ocular vascular disorder, photophobia, vitreous floaters.
- Gastrointestinal Disorders. Frequent: diarrhea. Infrequent: dysphagia, enterocolitis, eructation, esophagitis, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: gastric ulcer, intestinal obstruction, pancreatitis acute.
- General Disorders and Administration Site Conditions. Frequent: chest pain, edema, influenza-like illness. Infrequent: chest discomfort, chills, pyrexia.
- Hepatobiliary Disorders. Infrequent: gall bladder disorder.
- Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram abnormal, muscle enzyme increased, urine analysis abnormal.
- Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hyperlipidemia, hypokalemia. Rare: hypoglycemia.
- Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, muscle cramp, musculoskeletal pain, myalgia. Infrequent: arthritis, osteoporosis. Rare: myositis.
- Nervous System Disorders. Frequent: disturbance in attention, dizziness, sensory disturbance. Infrequent: amnesia, migraine, parosmia, psychomotor hyperactivity, restless legs syndrome, syncope, tremor. Rare: balance disorder, cerebrovascular accident, convulsion, dysarthria, facial palsy, mental impairment, multiple sclerosis, nystagmus, psychomotor skills impaired, transient ischemic attack, visual field defect.
- Psychiatric Disorders. Infrequent: disorientation, dissociation, libido decreased, mood swings, thinking abnormal. Rare: bradyphrenia, euphoric mood.
- Renal and Urinary Disorders. Frequent: polyuria. Infrequent: nephrolithiasis, nocturia, urethral syndrome, urine abnormality. Rare: renal failure acute, urinary retention.
- Reproductive System and Breast Disorders. Rare: sexual dysfunction. Frequent: menstrual disorder. Infrequent: erectile dysfunction.
- Respiratory, Thoracic and Mediastinal Disorders. Frequent: epistaxis, respiratory disorders. Infrequent: asthma. Rare: pleurisy, pulmonary embolism.
- Skin and Subcutaneous Tissue Disorders. Frequent: hyperhidrosis. Infrequent: acne, dry skin, eczema, erythema, psoriasis, urticaria. Rare: photosensitivity reaction.
- Vascular Disorders. Frequent: hot flush. Infrequent: thrombosis.
- CHANTIX has also been studied in postmarketing trials including (1) a trial conducted in patients with chronic obstructive pulmonary disease (COPD) (2) a trial conducted in generally healthy patients (similar to those in the premarketing studies) in which they were allowed to select a quit date between days 8 and 35 of treatment ("alternative quit date instruction trial"). (3) a trial conducted in patients with stable cardiovascular disease and (4) a trial conducted in patients with stable schizophrenia or schizoaffective disorder.
- Adverse events in the trial of patients with COPD and in the alternative quit date instruction trial were quantitatively and qualitatively similar to those observed in premarketing studies.
- In the trial of patients with stable cardiovascular disease, more types and a greater number of cardiovascular events were reported compared to premarketing studies. Treatment-emergent (on-treatment or 30 days after treatment) cardiovascular events reported with a frequency ≥ 1% in either treatment group in this study were angina pectoris (3.7% and 2.0% for varenicline and placebo, respectively), chest pain (2.5% vs. 2.3%), peripheral edema (2.0% vs. 1.1%), hypertension (1.4% vs. 2.6%), and palpitations (0.6 % vs. 1.1%). Deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by a blinded, independent committee. The following treatment-emergent adjudicated events occurred with a frequency ≥1% in either treatment group: nonfatal MI (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalization for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, the adjudicated events included need for coronary revascularization (2.0% vs. 0.6%), hospitalization for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52-week study.
- In the trial of patients with stable schizophrenia or schizoaffective disorder, 128 smokers on antipsychotic medication were randomized 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12-week non-drug follow-up. The most common adverse events in patients taking varenicline were nausea (24% vs. 14.0% on placebo), headache (11% vs. 19% on placebo) and vomiting (11% vs. 9% on placebo). Among reported neuropsychiatric adverse events, insomnia was the only event that occurred in either treatment group in ≥ 5% of subjects at a rate higher in the varenicline group than in placebo (10% vs. 5%). These common and neuropsychiatric adverse events occurred on treatment or within 30 days after the last dose of study drug. There was no consistent worsening of schizophrenia in either treatment group as measured by the Positive and Negative Syndrome Scale. There were no overall changes in extra-pyramidal signs, as measured by the Simpson-Angus Rating Scale. The Columbia-Suicide Severity Rating Scale was administered at baseline and at clinic visits during the treatment and non-treatment follow-up phases. Over half of the patients had a lifetime history of suicidal behavior and/or ideation (62% on varenicline vs. 51% on placebo), but at baseline, no patients in the varenicline group reported suicidal behavior and/or ideation vs. one patient in the placebo group (2%). Suicidal behavior and/or ideation were reported in 11% of the varenicline-treated and 9% of the placebo-treated patients during the treatment phase. During the post-treatment phase, suicidal behavior and/or ideation were reported in 11% of patients in the varenicline group and 5% of patients in the placebo group. Many of the patients reporting suicidal behavior and ideation in the follow-up phase had not reported such experiences in the treatment phase. However, no new suicidal ideation or behavior emerged in either treatment group shortly (within one week) after treatment discontinuation (a phenomenon noted in post-marketing reporting). There were no completed suicides. There was one suicide attempt in a varenicline-treated patient. The limited data available from this single smoking cessation study are not sufficient to allow conclusions to be drawn.
## Postmarketing Experience
- The following adverse events have been reported during post-approval use of CHANTIX. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- There have been reports of depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide in patients attempting to quit smoking while taking CHANTIX. Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients had known pre-existing psychiatric illness and not all had discontinued smoking.
- There have been reports of hypersensitivity reactions, including angioedema.
- There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients taking CHANTIX.
- There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking Chantix. In the majority of the reported cases, patients had pre-existing cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, based on temporal relationship between medication use and events, a contributory role of varenicline cannot be ruled out.
# Drug Interactions
- Based on varenicline characteristics and clinical experience to date, CHANTIX has no clinically meaningful pharmacokinetic drug interactions.
Use With Other Drugs for Smoking Cessation
- Safety and efficacy of CHANTIX in combination with other smoking cessation therapies have not been studied.
- Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers. The safety of the combination of bupropion and varenicline has not been established.
- Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo.
Effect of Smoking Cessation on Other Drugs
- Physiological changes resulting from smoking cessation, with or without treatment with CHANTIX, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of CHANTIX use in pregnant women. In animal studies, CHANTIX caused decreased fetal weights, increased auditory startle response, and decreased fertility in offspring. CHANTIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In reproductive and developmental toxicity studies, pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. These exposures were 36 (rats) and 50 (rabbits) times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 1 mg twice daily. While no fetal structural abnormalities occurred in either species, reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD based on AUC). Fetal weight reduction did not occur at animal exposures 23 times the human exposure at the MRHD based on AUC.
- In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. These resulted in exposures up to 36 times the human exposure (based on AUC) at the MRHD of 1 mg twice daily. Decreased fertility and increased auditory startle response occurred in offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Varenicline in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Varenicline during labor and delivery.
### Nursing Mothers
- It is not known whether CHANTIX is excreted in human milk. In animal studies varenicline was excreted in milk of lactating animals. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CHANTIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of CHANTIX in pediatric patients have not been established.
### Geriatic Use
- A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) for 7 consecutive days was similar to that of younger subjects. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function .
- No dosage adjustment is recommended for elderly patients.
### Gender
- There is no FDA guidance on the use of Varenicline with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Varenicline with respect to specific racial populations.
### Renal Impairment
- Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed. .
### Hepatic Impairment
- There is no FDA guidance on the use of Varenicline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Varenicline in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Varenicline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Usual Dosage for Adults
- Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.
- The patient should set a date to stop smoking. Begin CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.
- CHANTIX should be taken after eating and with a full glass of water.
- The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:
- Patients should be treated with CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.
- Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed.
- Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
Dosage in Special Populations
- Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated.
- Elderly and Patients with Impaired Hepatic Function: No dosage adjustment is necessary for patients with hepatic impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
DOSAGE FORMS AND STRENGTHS
- Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
### Monitoring
- There is limited information regarding Monitoring of Varenicline in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Varenicline in the drug label.
# Overdosage
- In case of overdose, standard supportive measures should be instituted as required.
- Varenicline has been shown to be dialyzed in patients with end stage renal disease, however, there is no experience in dialysis following overdose.
# Pharmacology
## Mechanism of Action
- Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.
- Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.
## Structure
- CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.
- Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazinobenzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 - C4H6O6. The chemical structure is:
- CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1mg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Varenicline in the drug label.
## Pharmacokinetics
- Absorption/Distribution: Maximum plasma concentrations of varenicline occur typically within 3–4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.
- Metabolism/Elimination: The elimination half-life of varenicline is approximately 24 hours. Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.
- Pharmacokinetics in Special Patient Populations: There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.
- Renal Impairment: Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD) undergoing a three-hour session of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were similar to those of healthy subjects receiving 1 mg twice daily. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis.
- Geriatric Patients: A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) for 7 consecutive days was similar to that of younger subjects.
- Pediatric Patients: Because the safety and effectiveness of CHANTIX in pediatric patients have not been established, CHANTIX is not recommended for use in patients under 18 years of age. Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0–24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population.
- Hepatic Impairment: Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.
- Drug-Drug Interactions: Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, and metformin. No clinically meaningful pharmacokinetic drug-drug interactions have been identified.
- In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.
- In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g., metformin ) are unlikely to be affected by varenicline.
- In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine ) may not necessitate a dose adjustment of CHANTIX as the increase in systemic exposure to CHANTIX is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHANTIX; therefore, a dose adjustment of CHANTIX would not be required.
- Metformin: When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.
- Cimetidine: Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.
- Digoxin: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers.
- Warfarin: Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics.
- Use with Other Drugs for Smoking Cessation:
- Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers.
- Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of adverse reactions was greater for the combination than for NRT alone.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis: Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats. There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on AUC). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n = 65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in female rats.
- Mutagenesis: Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes.
- Impairment of Fertility: There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1 mg twice daily). However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg twice daily. This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the maximum recommended human daily exposure based on AUC at 1 mg twice daily).
# Clinical Studies
- The efficacy of CHANTIX in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers (≥10 cigarettes per day) were treated with CHANTIX. In all clinical studies, abstinence from smoking was determined by patient self-report and verified by measurement of exhaled carbon monoxide (CO≤10 ppm) at weekly visits. Among the CHANTIX-treated patients enrolled in these studies, the completion rate was 65%. Except for the dose-ranging study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. Most patients enrolled in these trials were white (79–96%). All studies enrolled almost equal numbers of men and women. The average age of patients in these studies was 43 years. Patients on average had smoked about 21 cigarettes per day for an average of approximately 25 years. Patients set a date to stop smoking (target quit date) with dosing starting 1 week before this date.
- Three additional studies were conducted in patients with cardiovascular disease, in patients with chronic obstructive pulmonary disease, and in patients instructed to select their quit date within days 8 and 35 of treatment.
- In all studies, patients were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counseling at each weekly treatment visit according to Agency for Healthcare Research and Quality guidelines.
Initiation of Abstinence
- Study 1: This was a six-week dose-ranging study comparing CHANTIX to placebo. This study provided initial evidence that CHANTIX at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.
- Study 2: This study of 627 patients compared CHANTIX 1 mg per day and 2 mg per day with placebo. Patients were treated for 12 weeks (including one week titration) and then were followed for 40 weeks post-treatment. CHANTIX was given in two divided doses daily. Each dose of CHANTIX was given in two different regimens, with and without initial dose titration, to explore the effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis.
- Forty-five percent of patients receiving CHANTIX 1 mg per day (0.5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1). In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group.
- Study 3: This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of CHANTIX or placebo. After an initial one-week titration to a dose of 0.5 mg twice daily, patients could adjust their dosage as often as they wished between 0.5 mg once daily to 1 mg twice daily per day. Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less.
- Of the patients treated with CHANTIX, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group.
- Study 4 and Study 5: These identical double-blind studies compared CHANTIX 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo. Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. The CHANTIX dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients. Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded.
- In Study 4, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group.
- Similarly in Study 5, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group.
Urge to Smoke
- Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale "urge to smoke" item, CHANTIX reduced urge to smoke compared to placebo.
Long-Term Abstinence
- Studies 1 through 5 included 40 weeks of post-treatment follow-up. In each study, CHANTIX-treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo (Figure 2, Table 5).
- Study 6: This study assessed the effect of an additional 12 weeks of CHANTIX therapy on the likelihood of long-term abstinence. Patients in this study (n=1927) were treated with open-label CHANTIX 1 mg twice daily for 12 weeks. Patients who had stopped smoking for at least a week by Week 12 (n=1210) were then randomized to double-blind treatment with CHANTIX (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment.
- The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with CHANTIX (70%) than for patients switching to placebo (50%). Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (CHANTIX 54% versus placebo 39%).
- In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of CHANTIX; post-CHANTIX follow-up begins at Week 13 for the placebo group and Week 25 for the CHANTIX group. The y-axis represents the percentage of patients who had been abstinent for the last week of CHANTIX treatment and remained abstinent at the given timepoint.
Subjects with Cardiovascular and Chronic Obstructive Pulmonary Disease
- CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to CHANTIX 1 mg twice daily (n=353) or placebo (n=350) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%).
- CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC <70% and FEV1 ≥ 50% of predicted normal value. Subjects were randomized to CHANTIX 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%).
Alternative Instructions for Setting a Quit Date
- CHANTIX was evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment. Subjects were randomized 3:1 to CHANTIX 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post-treatment. Patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%).
# How Supplied
- CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. CHANTIX is supplied in the following package configurations:
## Storage
- Store at 25ºC (77ºF); excursions permitted to 15–30ºC (59–86ºF) (see USP Controlled Room Temperature).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-approved patient labeling (Medication Guide)
Initiate Treatment and Continue to Attempt to Quit if Lapse
- Instruct patients to set a date to quit smoking and to initiate CHANTIX treatment one week before the quit date. Alternatively, the patient can begin CHANTIX dosing and then set a date to quit smoking between days 8 and 35 of treatment. Encourage patients to continue to attempt to quit if they have early lapses after quit day .
How To Take
- Advise patients that CHANTIX should be taken after eating, and with a full glass of water.
Starting Week Dosage
- Instruct patients on how to titrate CHANTIX, beginning at a dose of 0.5 mg/day. Explain that one 0.5 mg tablet should be taken daily for the first three days, and that for the next four days, one 0.5 mg tablet should be taken in the morning and one 0.5 mg tablet should be taken in the evening.
Continuing Weeks Dosage
- Advise patients that, after the first seven days, the dose should be increased to one 1 mg tablet in the morning and one 1 mg tablet in the evening .
Dosage Adjustment for CHANTIX or Other Drugs
- Inform patients that nausea and insomnia are side effects of CHANTIX and are usually transient; however, advise patients that if they are persistently troubled by these symptoms, they should notify the prescribing physician so that a dose reduction can be considered.
- Inform patients that some drugs may require dose adjustment after quitting smoking.
Counseling and Support
- Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking.
Neuropsychiatric Symptoms
- Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking CHANTIX. If patients develop agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to discontinue CHANTIX and report these symptoms to their healthcare provider immediately.
History of Psychiatric Illness
- Encourage patients to reveal any history of psychiatric illness prior to initiating treatment.
Nicotine Withdrawal
- Inform patients that quitting smoking, with or without CHANTIX, may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of pre-existing psychiatric illness.
Angioedema
- Inform patients that there have been reports of angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.
Serious Skin Reactions
- Inform patients that serious skin reactions, such as Stevens-Johnson Syndrome and erythema multiforme, were reported by some patients taking CHANTIX. Advise patients to stop taking CHANTIX at the first sign of rash with mucosal lesions or skin reaction and contact a healthcare provider immediately.
Cardiovascular Events
- Patients should be instructed to notify their health care providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke.
Driving or Operating Machinery
- Advise patients to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them.
Vivid, Unusual, or Strange Dreams
- Inform patients that they may experience vivid, unusual or strange dreams during treatment with CHANTIX.
Pregnancy and Lactation
- Patients who are pregnant or breastfeeding or planning to become pregnant should be advised of: the risks of smoking to a pregnant mother and her developing baby, the potential risks of CHANTIX use during pregnancy and breastfeeding, and the benefits of smoking cessation with and without CHANTIX.
# Precautions with Alcohol
- Alcohol-Varenicline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Chantix,
Chantix Start Month Pak,
Chantix Starter Pack,
Chantix Starting Month Box.
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Varenicline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Black Box Warning
# Overview
Varenicline is a neurotransmitter agent that is FDA approved for the treatment of smoking cessation. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, abnormal (e.g., vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- Usual Dosage for Adults
- Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.
- The patient should set a date to stop smoking. Begin CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.
- CHANTIX should be taken after eating and with a full glass of water.
- The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:
- Patients should be treated with CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.
- Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed.
- Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
- Dosage in Special Populations
- Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated.
- Elderly and Patients with Impaired Hepatic Function: No dosage adjustment is necessary for patients with hepatic impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- DOSAGE FORMS AND STRENGTHS
- Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Varenicline in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Varenicline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Varenicline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Varenicline in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Varenicline in pediatric patients.
# Contraindications
- CHANTIX is contraindicated in patients with a known history of serious hypersensitivity reactions or skin reactions to CHANTIX.
# Warnings
Neuropsychiatric Symptoms and Suicidality
- Serious neuropsychiatric symptoms have been reported in patients being treated with CHANTIX. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking CHANTIX who continued to smoke. When symptoms were reported, most were during CHANTIX treatment, but some were following discontinuation of CHANTIX therapy.
- These events have occurred in patients with and without pre-existing psychiatric disease; some patients have experienced worsening of their psychiatric illnesses. All patients being treated with CHANTIX should be observed for neuropsychiatric symptoms or worsening of pre-existing psychiatric illness. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the premarketing studies of CHANTIX, and the safety and efficacy of CHANTIX in such patients has not been established. Limited data are available from a single smoking cessation study in patients with stable schizophrenia or schizoaffective disorder.
- Advise patients and caregivers that the patient should stop taking CHANTIX and contact a healthcare provider immediately if agitation, depressed mood, changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of CHANTIX was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
- The risks of CHANTIX should be weighed against the benefits of its use. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
Angioedema and Hypersensitivity Reactions
- There have been postmarketing reports of hypersensitivity reactions including angioedema in patients treated with CHANTIX. Clinical signs included swelling of the face, mouth (tongue, lips, and gums), extremities, and neck (throat and larynx). There were infrequent reports of life-threatening angioedema requiring emergent medical attention due to respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.
Serious Skin Reactions
- There have been postmarketing reports of rare but serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients using CHANTIX. As these skin reactions can be life-threatening, instruct patients to stop taking CHANTIX and contact a healthcare provider immediately at the first appearance of a skin rash with mucosal lesions or any other signs of hypersensitivity.
Cardiovascular Events
- In a placebo-controlled clinical trial of CHANTIX administered to patients with stable cardiovascular disease, with approximately 350 patients per treatment arm, all-cause and cardiovascular mortality was lower in patients treated with CHANTIX, but certain nonfatal cardiovascular events occurred more frequently in patients treated with CHANTIX than in patients treated with placebo. Table 1 below shows the incidence of deaths and of selected nonfatal serious cardiovascular events occurring more frequently in the CHANTIX arm compared to the placebo arm. These events were adjudicated by an independent blinded committee. Nonfatal serious cardiovascular events not listed occurred at the same incidence or more commonly in the placebo arm. Patients with more than one cardiovascular event of the same type are counted only once per row. Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina.
- A meta-analysis of 15 clinical trials of ≥ 12 weeks treatment duration, including 7002 patients (4190 CHANTIX, 2812 placebo), was conducted to systematically assess the cardiovascular safety of CHANTIX. The study in patients with stable cardiovascular disease described above was included in the meta-analysis. There were lower rates of all-cause mortality (CHANTIX 6 [0.14%]; placebo 7 [0.25%]) and cardiovascular mortality (CHANTIX 2 [0.05%]; placebo 2 [0.07%]) in the CHANTIX arms compared with the placebo arms in the meta-analysis.
- The key cardiovascular safety analysis included occurrence and timing of a composite endpoint of Major Adverse Cardiovascular Events (MACE), defined as cardiovascular death, nonfatal MI, and nonfatal stroke. These events included in the endpoint were adjudicated by a blinded, independent committee. Overall, a small number of MACE occurred in the trials included in the meta-analysis, as described in Table 2. These events occurred primarily in patients with known cardiovascular disease.
- The meta-analysis showed that exposure to CHANTIX resulted in a hazard ratio for MACE of 1.95 (95% confidence interval from 0.79 to 4.82) for patients up to 30 days after treatment; this is equivalent to an estimated increase of 6.3 MACE events per 1,000 patient-years of exposure. The meta-analysis showed higher rates of CV endpoints in patients on CHANTIX relative to placebo across different time frames and pre-specified sensitivity analyses, including various study groupings and CV outcomes. Although these findings were not statistically significant they were consistent. Because the number of events was small overall, the power for finding a statistically significant difference in a signal of this magnitude is low.
- CHANTIX was not studied in patients with unstable cardiovascular disease or cardiovascular events occurring within two months before screening. Patients should be advised to notify a health care provider of new or worsening symptoms of cardiovascular disease. The risks of CHANTIX should be weighed against the benefits of its use in smokers with cardiovascular disease. Smoking is an independent and major risk factor for cardiovascular disease. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo.
Accidental Injury
- There have been postmarketing reports of traffic accidents, near-miss incidents in traffic, or other accidental injuries in patients taking CHANTIX. In some cases, the patients reported somnolence, dizziness, loss of consciousness or difficulty concentrating that resulted in impairment, or concern about potential impairment, in driving or operating machinery. Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous activities until they know how CHANTIX may affect them.
Nausea
- Nausea was the most common adverse reaction reported with CHANTIX treatment. Nausea was generally described as mild or moderate and often transient; however, for some patients, it was persistent over several months. The incidence of nausea was dose-dependent. Initial dose-titration was beneficial in reducing the occurrence of nausea. For patients treated to the maximum recommended dose of 1 mg twice daily following initial dosage titration, the incidence of nausea was 30% compared with 10% in patients taking a comparable placebo regimen. In patients taking CHANTIX 0.5 mg twice daily following initial titration, the incidence was 16% compared with 11% for placebo. Approximately 3% of patients treated with CHANTIX 1 mg twice daily in studies involving 12 weeks of treatment discontinued treatment prematurely because of nausea. For patients with intolerable nausea, a dose reduction should be considered.
DRUG ABUSE AND DEPENDENCE
Controlled Substance
- Varenicline is not a controlled substance.
### Dependence
- Humans: Fewer than 1 out of 1000 patients reported euphoria in clinical trials with CHANTIX. At higher doses (greater than 2 mg), CHANTIX produced more frequent reports of gastrointestinal disturbances such as nausea and vomiting. There is no evidence of dose-escalation to maintain therapeutic effects in clinical studies, which suggests that tolerance does not develop. Abrupt discontinuation of CHANTIX was associated with an increase in irritability and sleep disturbances in up to 3% of patients. This suggests that, in some patients, varenicline may produce mild physical dependence which is not associated with addiction.
- In a human laboratory abuse liability study, a single oral dose of 1 mg varenicline did not produce any significant positive or negative subjective responses in smokers. In non-smokers, 1 mg varenicline produced an increase in some positive subjective effects, but this was accompanied by an increase in negative adverse effects, especially nausea. A single oral dose of 3 mg varenicline uniformly produced unpleasant subjective responses in both smokers and non-smokers.
- Animals: Studies in rodents have shown that varenicline produces behavioral responses similar to those produced by nicotine. In rats trained to discriminate nicotine from saline, varenicline produced full generalization to the nicotine cue. In self-administration studies, the degree to which varenicline substitutes for nicotine is dependent upon the requirement of the task. Rats trained to self-administer nicotine under easy conditions continued to self-administer varenicline to a degree comparable to that of nicotine; however in a more demanding task, rats self-administered varenicline to a lesser extent than nicotine. Varenicline pretreatment also reduced nicotine self-administration.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions were reported in postmarketing experience and are discussed in greater detail in other sections of the labeling:
- Neuropsychiatric symptoms and suicidality
- Angioedema and hypersensitivity reactions
- Accidental injury
- In the placebo-controlled studies, the most common adverse events associated with CHANTIX (>5% and twice the rate seen in placebo-treated patients) were nausea, abnormal (vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.
- The treatment discontinuation rate due to adverse events in patients dosed with 1 mg twice daily was 12% for CHANTIX, compared to 10% for placebo in studies of three months' treatment. In this group, the discontinuation rates that are higher than placebo for the most common adverse events in CHANTIX-treated patients were as follows: nausea (3% vs. 0.5% for placebo), insomnia (1.2% vs. 1.1% for placebo), and abnormal dreams (0.3% vs. 0.2% for placebo).
- Smoking cessation, with or without treatment, is associated with nicotine withdrawal symptoms and has also been associated with the exacerbation of underlying psychiatric illness.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- During the premarketing development of CHANTIX, over 4500 subjects were exposed to CHANTIX, with over 450 treated for at least 24 weeks and approximately 100 for a year. Most study participants were treated for 12 weeks or less.
- The most common adverse event associated with CHANTIX treatment is nausea, occurring in 30% of patients treated at the recommended dose, compared with 10% in patients taking a comparable placebo regimen.
- Table 3 shows the adverse events for CHANTIX and placebo in the 12-week fixed dose studies with titration in the first week [Studies 2 (titrated arm only), 4, and 5]. Adverse events were categorized using the Medical Dictionary for Regulatory Activities (MedDRA, Version 7.1).
- MedDRA High Level Group Terms (HLGT) reported in ≥ 5% of patients in the CHANTIX 1 mg twice daily dose group, and more commonly than in the placebo group, are listed, along with subordinate Preferred Terms (PT) reported in ≥ 1% of CHANTIX patients (and at least 0.5% more frequent than placebo). Closely related Preferred Terms such as 'Insomnia', 'Initial insomnia', 'Middle insomnia', 'Early morning awakening' were grouped, but individual patients reporting two or more grouped events are only counted once.
- The overall pattern and frequency of adverse events during the longer-term trials was similar to those described in Table 3, though several of the most common events were reported by a greater proportion of patients with long-term use (e.g., nausea was reported in 40% of patients treated with CHANTIX 1 mg twice daily in a one-year study, compared to 8% of placebo-treated patients).
- Following is a list of treatment-emergent adverse events reported by patients treated with CHANTIX during all clinical trials. The listing does not include those events already listed in the previous tables or elsewhere in labeling, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life-threatening.
- Blood and Lymphatic System Disorders. Infrequent: anemia, lymphadenopathy. Rare: leukocytosis, splenomegaly, thrombocytopenia.
- Cardiac Disorders. Infrequent: angina pectoris, arrhythmia, bradycardia, myocardial infarction, palpitations, tachycardia, ventricular extrasystoles. Rare: acute coronary syndrome, atrial fibrillation, cardiac flutter, cor pulmonale, coronary artery disease.
- Ear and Labyrinth Disorders. Infrequent: tinnitus, vertigo. Rare: deafness, Meniere's disease.
- Endocrine Disorders. Infrequent: thyroid gland disorders.
- Eye Disorders. Infrequent: conjunctivitis, dry eye, eye irritation, eye pain, vision blurred, visual disturbance. Rare: acquired night blindness, blindness transient, cataract subcapsular, ocular vascular disorder, photophobia, vitreous floaters.
- Gastrointestinal Disorders. Frequent: diarrhea. Infrequent: dysphagia, enterocolitis, eructation, esophagitis, gastritis, gastrointestinal hemorrhage, mouth ulceration. Rare: gastric ulcer, intestinal obstruction, pancreatitis acute.
- General Disorders and Administration Site Conditions. Frequent: chest pain, edema, influenza-like illness. Infrequent: chest discomfort, chills, pyrexia.
- Hepatobiliary Disorders. Infrequent: gall bladder disorder.
- Investigations. Frequent: liver function test abnormal, weight increased. Infrequent: electrocardiogram abnormal, muscle enzyme increased, urine analysis abnormal.
- Metabolism and Nutrition Disorders. Infrequent: diabetes mellitus, hyperlipidemia, hypokalemia. Rare: hypoglycemia.
- Musculoskeletal and Connective Tissue Disorders. Frequent: arthralgia, back pain, muscle cramp, musculoskeletal pain, myalgia. Infrequent: arthritis, osteoporosis. Rare: myositis.
- Nervous System Disorders. Frequent: disturbance in attention, dizziness, sensory disturbance. Infrequent: amnesia, migraine, parosmia, psychomotor hyperactivity, restless legs syndrome, syncope, tremor. Rare: balance disorder, cerebrovascular accident, convulsion, dysarthria, facial palsy, mental impairment, multiple sclerosis, nystagmus, psychomotor skills impaired, transient ischemic attack, visual field defect.
- Psychiatric Disorders. Infrequent: disorientation, dissociation, libido decreased, mood swings, thinking abnormal. Rare: bradyphrenia, euphoric mood.
- Renal and Urinary Disorders. Frequent: polyuria. Infrequent: nephrolithiasis, nocturia, urethral syndrome, urine abnormality. Rare: renal failure acute, urinary retention.
- Reproductive System and Breast Disorders. Rare: sexual dysfunction. Frequent: menstrual disorder. Infrequent: erectile dysfunction.
- Respiratory, Thoracic and Mediastinal Disorders. Frequent: epistaxis, respiratory disorders. Infrequent: asthma. Rare: pleurisy, pulmonary embolism.
- Skin and Subcutaneous Tissue Disorders. Frequent: hyperhidrosis. Infrequent: acne, dry skin, eczema, erythema, psoriasis, urticaria. Rare: photosensitivity reaction.
- Vascular Disorders. Frequent: hot flush. Infrequent: thrombosis.
- CHANTIX has also been studied in postmarketing trials including (1) a trial conducted in patients with chronic obstructive pulmonary disease (COPD) (2) a trial conducted in generally healthy patients (similar to those in the premarketing studies) in which they were allowed to select a quit date between days 8 and 35 of treatment ("alternative quit date instruction trial"). (3) a trial conducted in patients with stable cardiovascular disease and (4) a trial conducted in patients with stable schizophrenia or schizoaffective disorder.
- Adverse events in the trial of patients with COPD and in the alternative quit date instruction trial were quantitatively and qualitatively similar to those observed in premarketing studies.
- In the trial of patients with stable cardiovascular disease, more types and a greater number of cardiovascular events were reported compared to premarketing studies. Treatment-emergent (on-treatment or 30 days after treatment) cardiovascular events reported with a frequency ≥ 1% in either treatment group in this study were angina pectoris (3.7% and 2.0% for varenicline and placebo, respectively), chest pain (2.5% vs. 2.3%), peripheral edema (2.0% vs. 1.1%), hypertension (1.4% vs. 2.6%), and palpitations (0.6 % vs. 1.1%). Deaths and serious cardiovascular events occurring over the 52 weeks of the study (treatment emergent and non-treatment emergent) were adjudicated by a blinded, independent committee. The following treatment-emergent adjudicated events occurred with a frequency ≥1% in either treatment group: nonfatal MI (1.1% vs. 0.3% for varenicline and placebo, respectively), and hospitalization for angina pectoris (0.6% vs. 1.1%). During non-treatment follow up to 52 weeks, the adjudicated events included need for coronary revascularization (2.0% vs. 0.6%), hospitalization for angina pectoris (1.7% vs. 1.1%), and new diagnosis of peripheral vascular disease (PVD) or admission for a PVD procedure (1.4% vs. 0.6%). Some of the patients requiring coronary revascularization underwent the procedure as part of management of nonfatal MI and hospitalization for angina. Cardiovascular death occurred in 0.3% of patients in the varenicline arm and 0.6% of patients in the placebo arm over the course of the 52-week study.
- In the trial of patients with stable schizophrenia or schizoaffective disorder, 128 smokers on antipsychotic medication were randomized 2:1 to varenicline (1 mg twice daily) or placebo for 12 weeks with 12-week non-drug follow-up. The most common adverse events in patients taking varenicline were nausea (24% vs. 14.0% on placebo), headache (11% vs. 19% on placebo) and vomiting (11% vs. 9% on placebo). Among reported neuropsychiatric adverse events, insomnia was the only event that occurred in either treatment group in ≥ 5% of subjects at a rate higher in the varenicline group than in placebo (10% vs. 5%). These common and neuropsychiatric adverse events occurred on treatment or within 30 days after the last dose of study drug. There was no consistent worsening of schizophrenia in either treatment group as measured by the Positive and Negative Syndrome Scale. There were no overall changes in extra-pyramidal signs, as measured by the Simpson-Angus Rating Scale. The Columbia-Suicide Severity Rating Scale was administered at baseline and at clinic visits during the treatment and non-treatment follow-up phases. Over half of the patients had a lifetime history of suicidal behavior and/or ideation (62% on varenicline vs. 51% on placebo), but at baseline, no patients in the varenicline group reported suicidal behavior and/or ideation vs. one patient in the placebo group (2%). Suicidal behavior and/or ideation were reported in 11% of the varenicline-treated and 9% of the placebo-treated patients during the treatment phase. During the post-treatment phase, suicidal behavior and/or ideation were reported in 11% of patients in the varenicline group and 5% of patients in the placebo group. Many of the patients reporting suicidal behavior and ideation in the follow-up phase had not reported such experiences in the treatment phase. However, no new suicidal ideation or behavior emerged in either treatment group shortly (within one week) after treatment discontinuation (a phenomenon noted in post-marketing reporting). There were no completed suicides. There was one suicide attempt in a varenicline-treated patient. The limited data available from this single smoking cessation study are not sufficient to allow conclusions to be drawn.
## Postmarketing Experience
- The following adverse events have been reported during post-approval use of CHANTIX. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- There have been reports of depression, mania, psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide in patients attempting to quit smoking while taking CHANTIX. Smoking cessation with or without treatment is associated with nicotine withdrawal symptoms and the exacerbation of underlying psychiatric illness. Not all patients had known pre-existing psychiatric illness and not all had discontinued smoking.
- There have been reports of hypersensitivity reactions, including angioedema.
- There have also been reports of serious skin reactions, including Stevens-Johnson Syndrome and erythema multiforme, in patients taking CHANTIX.
- There have been reports of myocardial infarction (MI) and cerebrovascular accident (CVA) including ischemic and hemorrhagic events in patients taking Chantix. In the majority of the reported cases, patients had pre-existing cardiovascular disease and/or other risk factors. Although smoking is a risk factor for MI and CVA, based on temporal relationship between medication use and events, a contributory role of varenicline cannot be ruled out.
# Drug Interactions
- Based on varenicline characteristics and clinical experience to date, CHANTIX has no clinically meaningful pharmacokinetic drug interactions.
Use With Other Drugs for Smoking Cessation
- Safety and efficacy of CHANTIX in combination with other smoking cessation therapies have not been studied.
- Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers. The safety of the combination of bupropion and varenicline has not been established.
- Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of nausea, headache, vomiting, dizziness, dyspepsia, and fatigue was greater for the combination than for NRT alone. In this study, eight of twenty-two (36%) patients treated with the combination of varenicline and NRT prematurely discontinued treatment due to adverse events, compared to 1 of 17 (6%) of patients treated with NRT and placebo.
Effect of Smoking Cessation on Other Drugs
- Physiological changes resulting from smoking cessation, with or without treatment with CHANTIX, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of CHANTIX use in pregnant women. In animal studies, CHANTIX caused decreased fetal weights, increased auditory startle response, and decreased fertility in offspring. CHANTIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In reproductive and developmental toxicity studies, pregnant rats and rabbits received varenicline succinate during organogenesis at oral doses up to 15 and 30 mg/kg/day, respectively. These exposures were 36 (rats) and 50 (rabbits) times the human exposure (based on AUC) at the maximum recommended human dose (MRHD) of 1 mg twice daily. While no fetal structural abnormalities occurred in either species, reduced fetal weights occurred in rabbits at the highest dose (exposures 50 times the human exposure at the MRHD based on AUC). Fetal weight reduction did not occur at animal exposures 23 times the human exposure at the MRHD based on AUC.
- In a pre- and postnatal development study, pregnant rats received up to 15 mg/kg/day of oral varenicline succinate from organogenesis through lactation. These resulted in exposures up to 36 times the human exposure (based on AUC) at the MRHD of 1 mg twice daily. Decreased fertility and increased auditory startle response occurred in offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Varenicline in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Varenicline during labor and delivery.
### Nursing Mothers
- It is not known whether CHANTIX is excreted in human milk. In animal studies varenicline was excreted in milk of lactating animals. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from CHANTIX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of CHANTIX in pediatric patients have not been established.
### Geriatic Use
- A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) for 7 consecutive days was similar to that of younger subjects. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Varenicline is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.2)].
- No dosage adjustment is recommended for elderly patients.
### Gender
- There is no FDA guidance on the use of Varenicline with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Varenicline with respect to specific racial populations.
### Renal Impairment
- Varenicline is substantially eliminated by renal glomerular filtration along with active tubular secretion. Dose reduction is not required in patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), and for patients with end-stage renal disease undergoing hemodialysis, dosage adjustment is needed. [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
### Hepatic Impairment
- There is no FDA guidance on the use of Varenicline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Varenicline in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Varenicline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Usual Dosage for Adults
- Smoking cessation therapies are more likely to succeed for patients who are motivated to stop smoking and who are provided additional advice and support. Provide patients with appropriate educational materials and counseling to support the quit attempt.
- The patient should set a date to stop smoking. Begin CHANTIX dosing one week before this date. Alternatively, the patient can begin CHANTIX dosing and then quit smoking between days 8 and 35 of treatment.
- CHANTIX should be taken after eating and with a full glass of water.
- The recommended dose of CHANTIX is 1 mg twice daily following a 1-week titration as follows:
- Patients should be treated with CHANTIX for 12 weeks. For patients who have successfully stopped smoking at the end of 12 weeks, an additional course of 12 weeks' treatment with CHANTIX is recommended to further increase the likelihood of long-term abstinence.
- Patients who do not succeed in stopping smoking during 12 weeks of initial therapy, or who relapse after treatment, should be encouraged to make another attempt once factors contributing to the failed attempt have been identified and addressed.
- Consider a temporary or permanent dose reduction in patients who cannot tolerate the adverse effects of CHANTIX.
Dosage in Special Populations
- Patients with Impaired Renal Function: No dosage adjustment is necessary for patients with mild to moderate renal impairment. For patients with severe renal impairment (estimated creatinine clearance <30 mL/min), the recommended starting dose of CHANTIX is 0.5 mg once daily. The dose may then be titrated as needed to a maximum dose of 0.5 mg twice a day. For patients with end-stage renal disease undergoing hemodialysis, a maximum dose of 0.5 mg once daily may be administered if tolerated.
- Elderly and Patients with Impaired Hepatic Function: No dosage adjustment is necessary for patients with hepatic impairment. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
DOSAGE FORMS AND STRENGTHS
- Capsular, biconvex tablets: 0.5 mg (white to off-white, debossed with "Pfizer" on one side and "CHX 0.5" on the other side) and 1 mg (light blue, debossed with "Pfizer" on one side and "CHX 1.0" on the other side)
### Monitoring
- There is limited information regarding Monitoring of Varenicline in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Varenicline in the drug label.
# Overdosage
- In case of overdose, standard supportive measures should be instituted as required.
- Varenicline has been shown to be dialyzed in patients with end stage renal disease, however, there is no experience in dialysis following overdose.
# Pharmacology
## Mechanism of Action
- Varenicline binds with high affinity and selectivity at α4β2 neuronal nicotinic acetylcholine receptors. The efficacy of CHANTIX in smoking cessation is believed to be the result of varenicline's activity at α4β2 sub-type of the nicotinic receptor where its binding produces agonist activity, while simultaneously preventing nicotine binding to these receptors.
- Electrophysiology studies in vitro and neurochemical studies in vivo have shown that varenicline binds to α4β2 neuronal nicotinic acetylcholine receptors and stimulates receptor-mediated activity, but at a significantly lower level than nicotine. Varenicline blocks the ability of nicotine to activate α4β2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking. Varenicline is highly selective and binds more potently to α4β2 receptors than to other common nicotinic receptors (>500-fold α3β4, >3500-fold α7, >20,000-fold α1βγδ), or to non-nicotinic receptors and transporters (>2000-fold). Varenicline also binds with moderate affinity (Ki = 350 nM) to the 5-HT3 receptor.
## Structure
- CHANTIX tablets contain varenicline (as the tartrate salt), which is a partial agonist selective for α4β2 nicotinic acetylcholine receptor subtypes.
- Varenicline, as the tartrate salt, is a powder which is a white to off-white to slightly yellow solid with the following chemical name: 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3- h][3]benzazepine, (2R,3R)-2,3-dihydroxybutanedioate (1:1). It is highly soluble in water. Varenicline tartrate has a molecular weight of 361.35 Daltons, and a molecular formula of C13H13N3 • C4H6O6. The chemical structure is:
- CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each 1mg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base. The following inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Varenicline in the drug label.
## Pharmacokinetics
- Absorption/Distribution: Maximum plasma concentrations of varenicline occur typically within 3–4 hours after oral administration. Following administration of multiple oral doses of varenicline, steady-state conditions were reached within 4 days. Over the recommended dosing range, varenicline exhibits linear pharmacokinetics after single or repeated doses. In a mass balance study, absorption of varenicline was virtually complete after oral administration and systemic availability was ~90%. Oral bioavailability of varenicline is unaffected by food or time-of-day dosing. Plasma protein binding of varenicline is low (≤20%) and independent of both age and renal function.
- Metabolism/Elimination: The elimination half-life of varenicline is approximately 24 hours. Varenicline undergoes minimal metabolism, with 92% excreted unchanged in the urine. Renal elimination of varenicline is primarily through glomerular filtration along with active tubular secretion possibly via the organic cation transporter, OCT2.
- Pharmacokinetics in Special Patient Populations: There are no clinically meaningful differences in varenicline pharmacokinetics due to age, race, gender, smoking status, or use of concomitant medications, as demonstrated in specific pharmacokinetic studies and in population pharmacokinetic analyses.
- Renal Impairment: Varenicline pharmacokinetics were unchanged in subjects with mild renal impairment (estimated creatinine clearance >50 mL/min and ≤80 mL/min). In subjects with moderate renal impairment (estimated creatinine clearance ≥30 mL/min and ≤50 mL/min), varenicline exposure increased 1.5-fold compared with subjects with normal renal function (estimated creatinine clearance >80 mL/min). In subjects with severe renal impairment (estimated creatinine clearance <30 mL/min), varenicline exposure was increased 2.1-fold. In subjects with end-stage-renal disease (ESRD) undergoing a three-hour session of hemodialysis for three days a week, varenicline exposure was increased 2.7-fold following 0.5 mg once daily administration for 12 days. The plasma Cmax and AUC of varenicline noted in this setting were similar to those of healthy subjects receiving 1 mg twice daily. Additionally, in subjects with ESRD, varenicline was efficiently removed by hemodialysis.
- Geriatric Patients: A combined single- and multiple-dose pharmacokinetic study demonstrated that the pharmacokinetics of 1 mg varenicline given once daily or twice daily to 16 healthy elderly male and female smokers (aged 65–75 yrs) for 7 consecutive days was similar to that of younger subjects.
- Pediatric Patients: Because the safety and effectiveness of CHANTIX in pediatric patients have not been established, CHANTIX is not recommended for use in patients under 18 years of age. Single and multiple-dose pharmacokinetics of varenicline have been investigated in pediatric patients aged 12 to 17 years old (inclusive) and were approximately dose-proportional over the 0.5 mg to 2 mg daily dose range studied. Steady-state systemic exposure in adolescent patients of bodyweight >55 kg, as assessed by AUC (0–24), was comparable to that noted for the same doses in the adult population. When 0.5 mg BID was given, steady-state daily exposure of varenicline was, on average, higher (by approximately 40%) in adolescent patients with bodyweight ≤ 55 kg compared to that noted in the adult population.
- Hepatic Impairment: Due to the absence of significant hepatic metabolism, varenicline pharmacokinetics should be unaffected in patients with hepatic impairment.
- Drug-Drug Interactions: Drug interaction studies were performed with varenicline and digoxin, warfarin, transdermal nicotine, bupropion, cimetidine, and metformin. No clinically meaningful pharmacokinetic drug-drug interactions have been identified.
- In vitro studies demonstrated that varenicline does not inhibit the following cytochrome P450 enzymes (IC50 >6400 ng/mL): 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4/5. Also, in human hepatocytes in vitro, varenicline does not induce the cytochrome P450 enzymes 1A2 and 3A4.
- In vitro studies demonstrated that varenicline does not inhibit human renal transport proteins at therapeutic concentrations. Therefore, drugs that are cleared by renal secretion (e.g., metformin [see below]) are unlikely to be affected by varenicline.
- In vitro studies demonstrated the active renal secretion of varenicline is mediated by the human organic cation transporter OCT2. Co-administration with inhibitors of OCT2 (e.g., cimeditine [see below]) may not necessitate a dose adjustment of CHANTIX as the increase in systemic exposure to CHANTIX is not expected to be clinically meaningful. Furthermore, since metabolism of varenicline represents less than 10% of its clearance, drugs known to affect the cytochrome P450 system are unlikely to alter the pharmacokinetics of CHANTIX; therefore, a dose adjustment of CHANTIX would not be required.
- Metformin: When co-administered to 30 smokers, varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of metformin (500 mg twice daily), which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.
- Cimetidine: Co-administration of an OCT2 inhibitor, cimetidine (300 mg four times daily), with varenicline (2 mg single dose) to 12 smokers increased the systemic exposure of varenicline by 29% (90% CI: 21.5%, 36.9%) due to a reduction in varenicline renal clearance.
- Digoxin: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of digoxin administered as a 0.25 mg daily dose in 18 smokers.
- Warfarin: Varenicline (1 mg twice daily) did not alter the pharmacokinetics of a single 25 mg dose of (R, S)-warfarin in 24 smokers. Prothrombin time (INR) was not affected by varenicline. Smoking cessation itself may result in changes to warfarin pharmacokinetics.
- Use with Other Drugs for Smoking Cessation:
- Bupropion: Varenicline (1 mg twice daily) did not alter the steady-state pharmacokinetics of bupropion (150 mg twice daily) in 46 smokers.
- Nicotine replacement therapy (NRT): Although co-administration of varenicline (1 mg twice daily) and transdermal nicotine (21 mg/day) for up to 12 days did not affect nicotine pharmacokinetics, the incidence of adverse reactions was greater for the combination than for NRT alone.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenesis: Lifetime carcinogenicity studies were performed in CD-1 mice and Sprague-Dawley rats. There was no evidence of a carcinogenic effect in mice administered varenicline by oral gavage for 2 years at doses up to 20 mg/kg/day (47 times the maximum recommended human daily exposure based on AUC). Rats were administered varenicline (1, 5, and 15 mg/kg/day) by oral gavage for 2 years. In male rats (n = 65 per sex per dose group), incidences of hibernoma (tumor of the brown fat) were increased at the mid dose (1 tumor, 5 mg/kg/day, 23 times the maximum recommended human daily exposure based on AUC) and maximum dose (2 tumors, 15 mg/kg/day, 67 times the maximum recommended human daily exposure based on AUC). The clinical relevance of this finding to humans has not been established. There was no evidence of carcinogenicity in female rats.
- Mutagenesis: Varenicline was not genotoxic, with or without metabolic activation, in the following assays: Ames bacterial mutation assay; mammalian CHO/HGPRT assay; and tests for cytogenetic aberrations in vivo in rat bone marrow and in vitro in human lymphocytes.
- Impairment of Fertility: There was no evidence of impairment of fertility in either male or female Sprague-Dawley rats administered varenicline succinate up to 15 mg/kg/day (67 and 36 times, respectively, the maximum recommended human daily exposure based on AUC at 1 mg twice daily). However, a decrease in fertility was noted in the offspring of pregnant rats who were administered varenicline succinate at an oral dose of 15 mg/kg/day (36 times the maximum recommended human daily exposure based on AUC at 1 mg twice daily. This decrease in fertility in the offspring of treated female rats was not evident at an oral dose of 3 mg/kg/day (9 times the maximum recommended human daily exposure based on AUC at 1 mg twice daily).
# Clinical Studies
- The efficacy of CHANTIX in smoking cessation was demonstrated in six clinical trials in which a total of 3659 chronic cigarette smokers (≥10 cigarettes per day) were treated with CHANTIX. In all clinical studies, abstinence from smoking was determined by patient self-report and verified by measurement of exhaled carbon monoxide (CO≤10 ppm) at weekly visits. Among the CHANTIX-treated patients enrolled in these studies, the completion rate was 65%. Except for the dose-ranging study (Study 1) and the maintenance of abstinence study (Study 6), patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. Most patients enrolled in these trials were white (79–96%). All studies enrolled almost equal numbers of men and women. The average age of patients in these studies was 43 years. Patients on average had smoked about 21 cigarettes per day for an average of approximately 25 years. Patients set a date to stop smoking (target quit date) with dosing starting 1 week before this date.
- Three additional studies were conducted in patients with cardiovascular disease, in patients with chronic obstructive pulmonary disease, and in patients instructed to select their quit date within days 8 and 35 of treatment.
- In all studies, patients were provided with an educational booklet on smoking cessation and received up to 10 minutes of smoking cessation counseling at each weekly treatment visit according to Agency for Healthcare Research and Quality guidelines.
Initiation of Abstinence
- Study 1: This was a six-week dose-ranging study comparing CHANTIX to placebo. This study provided initial evidence that CHANTIX at a total dose of 1 mg per day or 2 mg per day was effective as an aid to smoking cessation.
- Study 2: This study of 627 patients compared CHANTIX 1 mg per day and 2 mg per day with placebo. Patients were treated for 12 weeks (including one week titration) and then were followed for 40 weeks post-treatment. CHANTIX was given in two divided doses daily. Each dose of CHANTIX was given in two different regimens, with and without initial dose titration, to explore the effect of different dosing regimens on tolerability. For the titrated groups, dosage was titrated up over the course of one week, with full dosage achieved starting with the second week of dosing. The titrated and nontitrated groups were pooled for efficacy analysis.
- Forty-five percent of patients receiving CHANTIX 1 mg per day (0.5 mg twice daily) and 51% of patients receiving 2 mg per day (1 mg twice daily) had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% of patients in the placebo group (Figure 1). In addition, 31% of the 1 mg per day group and 31% of the 2 mg per day group were continuously abstinent from one week after TQD through the end of treatment as compared to 8% of the placebo group.
- Study 3: This flexible-dosing study of 312 patients examined the effect of a patient-directed dosing strategy of CHANTIX or placebo. After an initial one-week titration to a dose of 0.5 mg twice daily, patients could adjust their dosage as often as they wished between 0.5 mg once daily to 1 mg twice daily per day. Sixty-nine percent of patients titrated to the maximum allowable dose at any time during the study. For 44% of patients, the modal dose selected was 1 mg twice daily; for slightly over half of the study participants, the modal dose selected was 1 mg/day or less.
- Of the patients treated with CHANTIX, 40% had CO-confirmed continuous abstinence during weeks 9 through 12 compared to 12% in the placebo group. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 9% of the placebo group.
- Study 4 and Study 5: These identical double-blind studies compared CHANTIX 2 mg per day, bupropion sustained-release (SR) 150 mg twice daily, and placebo. Patients were treated for 12 weeks and then were followed for 40 weeks post-treatment. The CHANTIX dosage of 1 mg twice daily was achieved using a titration of 0.5 mg once daily for the initial 3 days followed by 0.5 mg twice daily for the next 4 days. The bupropion SR dosage of 150 mg twice daily was achieved using a 3-day titration of 150 mg once daily. Study 4 enrolled 1022 patients and Study 5 enrolled 1023 patients. Patients inappropriate for bupropion treatment or patients who had previously used bupropion were excluded.
- In Study 4, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (17%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 12% of the placebo group and 23% of the bupropion SR group.
- Similarly in Study 5, patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (44%) compared to patients treated with bupropion SR (30%) or placebo (18%). The bupropion SR quit rate was also superior to placebo. In addition, 29% of the CHANTIX group were continuously abstinent from one week after TQD through the end of treatment as compared to 11% of the placebo group and 21% of the bupropion SR group.
Urge to Smoke
- Based on responses to the Brief Questionnaire of Smoking Urges and the Minnesota Nicotine Withdrawal scale "urge to smoke" item, CHANTIX reduced urge to smoke compared to placebo.
Long-Term Abstinence
- Studies 1 through 5 included 40 weeks of post-treatment follow-up. In each study, CHANTIX-treated patients were more likely to maintain abstinence throughout the follow-up period than were patients treated with placebo (Figure 2, Table 5).
- Study 6: This study assessed the effect of an additional 12 weeks of CHANTIX therapy on the likelihood of long-term abstinence. Patients in this study (n=1927) were treated with open-label CHANTIX 1 mg twice daily for 12 weeks. Patients who had stopped smoking for at least a week by Week 12 (n=1210) were then randomized to double-blind treatment with CHANTIX (1 mg twice daily) or placebo for an additional 12 weeks and then followed for 28 weeks post-treatment.
- The continuous abstinence rate from Week 13 through Week 24 was higher for patients continuing treatment with CHANTIX (70%) than for patients switching to placebo (50%). Superiority to placebo was also maintained during 28 weeks post-treatment follow-up (CHANTIX 54% versus placebo 39%).
- In Figure 3 below, the x-axis represents the study week for each observation, allowing a comparison of groups at similar times after discontinuation of CHANTIX; post-CHANTIX follow-up begins at Week 13 for the placebo group and Week 25 for the CHANTIX group. The y-axis represents the percentage of patients who had been abstinent for the last week of CHANTIX treatment and remained abstinent at the given timepoint.
Subjects with Cardiovascular and Chronic Obstructive Pulmonary Disease
- CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged 35 to 75 years with stable, documented cardiovascular disease (diagnoses other than, or in addition to, hypertension) that had been diagnosed for more than 2 months. Subjects were randomized to CHANTIX 1 mg twice daily (n=353) or placebo (n=350) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (47%) compared to subjects treated with placebo (14%) and from week 9 through 52 (20%) compared to subjects treated with placebo (7%).
- CHANTIX was evaluated in a randomized, double-blind, placebo-controlled study of subjects aged ≥ 35 years with mild-to-moderate COPD with post-bronchodilator FEV1/FVC <70% and FEV1 ≥ 50% of predicted normal value. Subjects were randomized to CHANTIX 1 mg twice daily (N=223) or placebo (N=237) for a treatment of 12 weeks and then were followed for 40 weeks post-treatment. Subjects treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (41%) compared to subjects treated with placebo (9%) and from week 9 through 52 (19%) compared to subjects treated with placebo (6%).
Alternative Instructions for Setting a Quit Date
- CHANTIX was evaluated in a double-blind, placebo-controlled trial where patients were instructed to select a target quit date between Day 8 and Day 35 of treatment. Subjects were randomized 3:1 to CHANTIX 1 mg twice daily (N=486) or placebo (N=165) for 12 weeks of treatment and followed for another 12 weeks post-treatment. Patients treated with CHANTIX had a superior rate of CO-confirmed abstinence during weeks 9 through 12 (54%) compared to patients treated with placebo (19%) and from weeks 9 through 24 (35%) compared to subjects treated with placebo (13%).
# How Supplied
- CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer" on one side and "CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer" on one side and "CHX 1.0" on the other side. CHANTIX is supplied in the following package configurations:
## Storage
- Store at 25ºC (77ºF); excursions permitted to 15–30ºC (59–86ºF) (see USP Controlled Room Temperature).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-approved patient labeling (Medication Guide)
Initiate Treatment and Continue to Attempt to Quit if Lapse
- Instruct patients to set a date to quit smoking and to initiate CHANTIX treatment one week before the quit date. Alternatively, the patient can begin CHANTIX dosing and then set a date to quit smoking between days 8 and 35 of treatment. Encourage patients to continue to attempt to quit if they have early lapses after quit day [see Dosage and Administration (2.1)].
How To Take
- Advise patients that CHANTIX should be taken after eating, and with a full glass of water.
Starting Week Dosage
- Instruct patients on how to titrate CHANTIX, beginning at a dose of 0.5 mg/day. Explain that one 0.5 mg tablet should be taken daily for the first three days, and that for the next four days, one 0.5 mg tablet should be taken in the morning and one 0.5 mg tablet should be taken in the evening.
Continuing Weeks Dosage
- Advise patients that, after the first seven days, the dose should be increased to one 1 mg tablet in the morning and one 1 mg tablet in the evening [see Dosage and Administration (2.1)].
Dosage Adjustment for CHANTIX or Other Drugs
- Inform patients that nausea and insomnia are side effects of CHANTIX and are usually transient; however, advise patients that if they are persistently troubled by these symptoms, they should notify the prescribing physician so that a dose reduction can be considered.
- Inform patients that some drugs may require dose adjustment after quitting smoking.
Counseling and Support
- Provide patients with educational materials and necessary counseling to support an attempt at quitting smoking.
Neuropsychiatric Symptoms
- Inform patients that some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation and suicide when attempting to quit smoking while taking CHANTIX. If patients develop agitation, hostility, depressed mood, or changes in behavior or thinking that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to discontinue CHANTIX and report these symptoms to their healthcare provider immediately.
History of Psychiatric Illness
- Encourage patients to reveal any history of psychiatric illness prior to initiating treatment.
Nicotine Withdrawal
- Inform patients that quitting smoking, with or without CHANTIX, may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of pre-existing psychiatric illness.
Angioedema
- Inform patients that there have been reports of angioedema, with swelling of the face, mouth (lip, gum, tongue) and neck (larynx and pharynx) that can lead to life-threatening respiratory compromise. Instruct patients to discontinue CHANTIX and immediately seek medical care if they experience these symptoms.
Serious Skin Reactions
- Inform patients that serious skin reactions, such as Stevens-Johnson Syndrome and erythema multiforme, were reported by some patients taking CHANTIX. Advise patients to stop taking CHANTIX at the first sign of rash with mucosal lesions or skin reaction and contact a healthcare provider immediately.
Cardiovascular Events
- Patients should be instructed to notify their health care providers of symptoms of new or worsening cardiovascular events and to seek immediate medical attention if they experience signs and symptoms of myocardial infarction or stroke.
Driving or Operating Machinery
- Advise patients to use caution driving or operating machinery until they know how quitting smoking and/or varenicline may affect them.
Vivid, Unusual, or Strange Dreams
- Inform patients that they may experience vivid, unusual or strange dreams during treatment with CHANTIX.
Pregnancy and Lactation
- Patients who are pregnant or breastfeeding or planning to become pregnant should be advised of: the risks of smoking to a pregnant mother and her developing baby, the potential risks of CHANTIX use during pregnancy and breastfeeding, and the benefits of smoking cessation with and without CHANTIX.
# Precautions with Alcohol
- Alcohol-Varenicline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Chantix,
Chantix Start Month Pak,
Chantix Starter Pack,
Chantix Starting Month Box.
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Varenicline | |
e06abab7f22c7b738ff1cb6896497c7cdbf6cf0d | wikidoc | Varicoscele | Varicoscele
Varicosele is a varicose condition of veins of the spermatic cord or the ovaries, forming a soft tumor.
Related: Varicosele
# Overview
Varicocele is a mass of enlarged veins that develops in the spermatic cord, which leads from the testicles (testes ) up through a passageway in the lower abdominal wall (systeminguinal canal) to the circulatory system. The spermatic cord is made up of blood vessels, lymphatic vessels, nerves, and the duct that carries sperm from the body (vas deferens). If the valves that regulate bloodflow from these veins become defective, blood does not circulate out of the testicles efficiently, which causes swelling in the veins above and behind the testicles.
A varicocele can develop in one testicle or both, but in about 85% of cases it develops in the left testicle. The left spermatic vein drains into the renal vein between the superior mesenteric artery and the aorta; these two arteries can compress the renal vein and thus impede bloodflow from the spermatic vein. The right spermatic vein drains into the vein that returns blood to the heart (vena cava) and develops varicocele less often. A one-sided (unilateral) varicocele can affect either testicle.
Because of the impaired circulation of blood created by a varicocele, the blood does not cool as it does normally. The increased temperature of the blood raises the temperature of the testes, which is believed to contribute to infertility, as heat can damage or destroy sperm. The increased temperature may also impede production of new, healthy sperm.
# Incidence and Prevalence
Incidence of varicocele is 10-20% and is highest in men between the ages of 15 and 25. The sudden appearance of varicocele in an older man may indicate a renal tumor blocking the spermatic vein.
Approximately 40% of infertile men have a varicocele and among men with secondary infertility—those who have fathered a child but are no longer able to do so—prevalence may be as high as 80%.
# Causes
A varicocele develops when the valve that regulates bloodflow from the vein into the main circulatory system becomes damaged or defective. Inefficient blood flow causes enlargement (dilation) of the vein.
# Signs and Symptoms
Most men who have a varicocele have no symptoms. Asymptomatic (i.e., symptom-free) cases are often diagnosed during a routine physical examination. Signs and symptoms may include the following:
Testicular pain
Feeling of heaviness in the testicle(s)
Infertility
Shrinkage (atrophy) of the testicle(s)
Visible or palpable (able to be felt) enlarged vein
Recurrent or constant discomfort or pain in the genital region should be reported to a urologist or primary care physician to determine the cause.
# Diagnosis
Large varicoceles may be seen with the naked eye. Medium-sized varicoceles may be detected during physical examination by feeling (palpating) the area. A patient suspected of having a varicocele should be examined while standing up, as a varicocele is more prominent in this position than in the supine (i.e., lying down, face up) position. Small varicoceles may be discovered by a physician using one of the following procedures.
# Treatment
If the patient is asymptomatic or the symptoms are mild and infertility is not an issue, the condition can be managed by wearing an athletic supporter or snug-fitting underwear to provide the scrotum with support.
# Surgery
If the varicocele causes pain or atrophy, if it damages the testicle(s), or if the condition is causing infertility, surgery may be recommended. Most varicoceles can be corrected through a surgical procedure called varicocelectomy (i.e., surgically "tying off" the affected spermatic veins). The following methods are used.
Surgical ligation usually requires general or reginal anesthesia. In this procedure, a 2- to 3-inch incision is made in the groin or lower abdomen, the affected veins are located visually, and the surgeon cuts the veins and ties them off above the varicocele to reroute the blood through unaffected veins. A incision in the groin (transinguinal) is commonly used and a lower abdomen (retroperitoneal) incision is used in patients with scar tissue from a prior varicocelectomy or hernia repair. Surgery can be performed on an in- or outpatient basis. The patient typically can resume light activity within a week and strenuous activity in about 6 weeks.
Embolization is a nonsurgical procedure that takes about an hour and a half. A small tube (catheter) is inserted into a small incision in the groin to block the flow of blood to the varicocele. Venography is used to highlight the varicocele on x-ray and to visually guide the catheter. The catheter is then used to push tiny coils into place to block the blood flow to the dilated vein. This eases the pressure, reduces enlargement, and restores normal circulation. Light sedation, sometimes called "twilight anesthesia," is used during the procedure; the patient does not lose consciousness. Stitches are not needed. Normal activity is usually resumed within 2 days.
Laparoscopy is a technique in which the surgeon inserts a tiny camera attached to a long cylindrical tube into the abdominal cavity through a small incision. Using the camera to locate the varicocele, the surgeon then inserts other instruments through the same incision to isolate and tie off the dilated veins. This technique requires a smaller incision than surgical ligation and is sometimes regarded as less invasive. The laparoscope, however, can sometimes damage abdominal organs, which is not a risk factor in open surgery. The procedure takes about 2 hours and recovery about 2 days.
# Prognosis
Between 5% and 20% of patients experience a recurrence. In such cases, the procedure usually is repeated. Another 2% to 5% develop a condition called hydrocele, a fluid-filled cyst that forms around the testicle. Minor surgery is used to correct this problem.
About 50% of men who undergo varicocelectomy to correct infertility father children within the first year. It takes about 90 days for a sufficient quantity of new sperm to be produced to permit fertilization. Semen analysis usually is done at 3- and 6-month intervals after the operation. (see Male Infertility).
If the patient is being examined for suspected infertility, the physician usually performs a comparative analysis of semen samples. Infertility caused by a varicocele typically produces a consistent pattern of incompletely developed, damaged, dead, or dying sperm.
# Naturopathic Treatment
A low fiber, highly refined diet—one that relies heavily on white flour products, sugar, and processed foods rather than fresh vegetables, whole grains, and fruits—is thought to be a contributing factor to varicocele formation. A lack of dietary fiber may slow down the bowels and contribute to constipation by hardening and drying the stool. Constipation stresses the pelvic floor by putting pressure on the veins when the bowels move. This repeated pressure strains the vessel walls and may damage vessel tissue.
Another contributing factor to varicocele formation is the lack of flavinoid-rich foods. Flavonoids, which are found in abundance in fresh vegetables and fruits, have been shown to contribute to the structural integrity of blood vessels.
# Diet Recommendations
# Supplemental Nutrition
# Herbal Therapeutics
Herbal remedies usually do not have side effects associated with regular use at the suggested doses. Rarely, an herb at the prescribed dose causes stomach upset or headache. This may reflect the purity of the preparation or added ingredients such as synthetic binders or fillers. For this reason it is recommended that you use only high quality, standardized extract formulas.
If possible, consult with a natural health practitioner such as a holistic medical doctor or licensed naturopathic physician before starting any alternative treatment plan. As with all medications, more is not better and overdosing can lead to serious illness and, in rare cases, death.
The following herbs may tone, strengthen, and improve the function of veins:
# Physical Medicine
Kegel exercises to improve blood flow and muscle tone. | Varicoscele
Varicosele is a varicose condition of veins of the spermatic cord or the ovaries, forming a soft tumor.
Related: Varicosele
# Overview
Varicocele is a mass of enlarged veins that develops in the spermatic cord, which leads from the testicles (testes ) up through a passageway in the lower abdominal wall (systeminguinal canal) to the circulatory system. The spermatic cord is made up of blood vessels, lymphatic vessels, nerves, and the duct that carries sperm from the body (vas deferens). If the valves that regulate bloodflow from these veins become defective, blood does not circulate out of the testicles efficiently, which causes swelling in the veins above and behind the testicles.
A varicocele can develop in one testicle or both, but in about 85% of cases it develops in the left testicle. The left spermatic vein drains into the renal vein between the superior mesenteric artery and the aorta; these two arteries can compress the renal vein and thus impede bloodflow from the spermatic vein. The right spermatic vein drains into the vein that returns blood to the heart (vena cava) and develops varicocele less often. A one-sided (unilateral) varicocele can affect either testicle.
Because of the impaired circulation of blood created by a varicocele, the blood does not cool as it does normally. The increased temperature of the blood raises the temperature of the testes, which is believed to contribute to infertility, as heat can damage or destroy sperm. The increased temperature may also impede production of new, healthy sperm.
# Incidence and Prevalence
Incidence of varicocele is 10-20% and is highest in men between the ages of 15 and 25. The sudden appearance of varicocele in an older man may indicate a renal tumor blocking the spermatic vein.
Approximately 40% of infertile men have a varicocele and among men with secondary infertility—those who have fathered a child but are no longer able to do so—prevalence may be as high as 80%.
# Causes
A varicocele develops when the valve that regulates bloodflow from the vein into the main circulatory system becomes damaged or defective. Inefficient blood flow causes enlargement (dilation) of the vein.
# Signs and Symptoms
Most men who have a varicocele have no symptoms. Asymptomatic (i.e., symptom-free) cases are often diagnosed during a routine physical examination. Signs and symptoms may include the following:
Testicular pain
Feeling of heaviness in the testicle(s)
Infertility
Shrinkage (atrophy) of the testicle(s)
Visible or palpable (able to be felt) enlarged vein
Recurrent or constant discomfort or pain in the genital region should be reported to a urologist or primary care physician to determine the cause.
# Diagnosis
Large varicoceles may be seen with the naked eye. Medium-sized varicoceles may be detected during physical examination by feeling (palpating) the area. A patient suspected of having a varicocele should be examined while standing up, as a varicocele is more prominent in this position than in the supine (i.e., lying down, face up) position. Small varicoceles may be discovered by a physician using one of the following procedures.
# Treatment
If the patient is asymptomatic or the symptoms are mild and infertility is not an issue, the condition can be managed by wearing an athletic supporter or snug-fitting underwear to provide the scrotum with support.
# Surgery
If the varicocele causes pain or atrophy, if it damages the testicle(s), or if the condition is causing infertility, surgery may be recommended. Most varicoceles can be corrected through a surgical procedure called varicocelectomy (i.e., surgically "tying off" the affected spermatic veins). The following methods are used.
Surgical ligation usually requires general or reginal anesthesia. In this procedure, a 2- to 3-inch incision is made in the groin or lower abdomen, the affected veins are located visually, and the surgeon cuts the veins and ties them off above the varicocele to reroute the blood through unaffected veins. A incision in the groin (transinguinal) is commonly used and a lower abdomen (retroperitoneal) incision is used in patients with scar tissue from a prior varicocelectomy or hernia repair. Surgery can be performed on an in- or outpatient basis. The patient typically can resume light activity within a week and strenuous activity in about 6 weeks.
Embolization is a nonsurgical procedure that takes about an hour and a half. A small tube (catheter) is inserted into a small incision in the groin to block the flow of blood to the varicocele. Venography is used to highlight the varicocele on x-ray and to visually guide the catheter. The catheter is then used to push tiny coils into place to block the blood flow to the dilated vein. This eases the pressure, reduces enlargement, and restores normal circulation. Light sedation, sometimes called "twilight anesthesia," is used during the procedure; the patient does not lose consciousness. Stitches are not needed. Normal activity is usually resumed within 2 days.
Laparoscopy is a technique in which the surgeon inserts a tiny camera attached to a long cylindrical tube into the abdominal cavity through a small incision. Using the camera to locate the varicocele, the surgeon then inserts other instruments through the same incision to isolate and tie off the dilated veins. This technique requires a smaller incision than surgical ligation and is sometimes regarded as less invasive. The laparoscope, however, can sometimes damage abdominal organs, which is not a risk factor in open surgery. The procedure takes about 2 hours and recovery about 2 days.
# Prognosis
Between 5% and 20% of patients experience a recurrence. In such cases, the procedure usually is repeated. Another 2% to 5% develop a condition called hydrocele, a fluid-filled cyst that forms around the testicle. Minor surgery is used to correct this problem.
About 50% of men who undergo varicocelectomy to correct infertility father children within the first year. It takes about 90 days for a sufficient quantity of new sperm to be produced to permit fertilization. Semen analysis usually is done at 3- and 6-month intervals after the operation. (see Male Infertility).
If the patient is being examined for suspected infertility, the physician usually performs a comparative analysis of semen samples. Infertility caused by a varicocele typically produces a consistent pattern of incompletely developed, damaged, dead, or dying sperm.
# Naturopathic Treatment
A low fiber, highly refined diet—one that relies heavily on white flour products, sugar, and processed foods rather than fresh vegetables, whole grains, and fruits—is thought to be a contributing factor to varicocele formation. A lack of dietary fiber may slow down the bowels and contribute to constipation by hardening and drying the stool. Constipation stresses the pelvic floor by putting pressure on the veins when the bowels move. This repeated pressure strains the vessel walls and may damage vessel tissue.
Another contributing factor to varicocele formation is the lack of flavinoid-rich foods. Flavonoids, which are found in abundance in fresh vegetables and fruits, have been shown to contribute to the structural integrity of blood vessels.
# Diet Recommendations
# Supplemental Nutrition
# Herbal Therapeutics
Herbal remedies usually do not have side effects associated with regular use at the suggested doses. Rarely, an herb at the prescribed dose causes stomach upset or headache. This may reflect the purity of the preparation or added ingredients such as synthetic binders or fillers. For this reason it is recommended that you use only high quality, standardized extract formulas.
If possible, consult with a natural health practitioner such as a holistic medical doctor or licensed naturopathic physician before starting any alternative treatment plan. As with all medications, more is not better and overdosing can lead to serious illness and, in rare cases, death.
The following herbs may tone, strengthen, and improve the function of veins:
# Physical Medicine
Kegel exercises to improve blood flow and muscle tone.
# External links
- http://www.urologychannel.com/varicocele/index.shtml
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Varicoscele | |
59498af8eba077b988b7a455a0f9aaa0648ff795 | wikidoc | Vasodilator | Vasodilator
A vasodilator is a drug or chemical that relaxes the smooth muscle in blood vessels, which causes them to dilate. Dilation of arterial blood vessels (mainly arterioles) lead to a decrease in blood pressure.
# Function
Vasodilation directly affects the relationship between Mean Arterial Pressure and Cardiac Output and Total Peripheral Resistance (TPR). Mathematically, cardiac output is computed by multiplying the heart rate (in beats/minute) and the stroke volume (the volume of blood ejected during systole). TPR depends on several factors including the length of the vessel, the viscosity of blood (determined by hematocrit), and the diameter of the blood vessel. The latter is the most important variable in determining resistance. An increase in either of these physiological components (cardiac output or TPR) cause a rise in the mean arterial pressure. Vasodilators work to decrease TPR and blood pressure through relaxation of smooth muscle cells in the tunica media layer of large arteries and smaller arterioles.
Vasodilation occurs in superficial blood vessels of warm-blooded animals when their ambient environment is hot; this process diverts the flow of heated blood to the skin of the animal, where heat can be more easily released into the atmosphere. The opposite physiological process is vasoconstriction. These processes are naturally modulated by local paracrine agents from endothelial cells (e.g bradykinin, adenosine), as well as an organism's Autonomic Nervous System and adrenal glands, both of which secrete catecholamines such as norepinephrine and epinephrine, respectively.
# Examples and individual mechanisms
Vasodilation is a result of relaxation in smooth muscle surrounding the blood vessels. This relaxation, in turn, relies on removing the stimulus for contraction, which depends predominately on intracellular calcium ion concentrations and phosphorylation of myosin light chain (MLC). Thus, vasodilation mainly works by either by lowering intracellular calcium concentration or dephosphorylation of MLC. This includes stimulation of myosin light chain phosphatase and induction of calcium symporters and antiporters that pump calcium ions out of the intracellular compartment. This is accomplished through retuptake of ions into the sarcoplasmic reticulum via exchangers and expulsion across the plasma membrane. The specific mechanisms to accomplish these effects varies from vasodilator to vasodilator.
These may be grouped as endogenous and exogenous vasodilators;
## Endogenous
## Exogenous vasodilators
- Absence of high levels of environmental noise
- Absence of high levels of illumination
- Adenocard - Adenosine agonist, primarily used as an anti-arrhythmic.
- Alpha blockers (block the vasoconstricting effect of adrenaline).
- Amyl nitrite and other nitrites are often used recreationally as a vasodilator, causing lightheadedness and a euphoric feeling.
- Atrial natriuretic peptide (ANP) - a weak vasodilator.
- Ethanol
- Histamine-inducers
Complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophil granulocytes.
- Complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophil granulocytes.
- Nitric oxide inducers
Glyceryl trinitrate (commonly known as Nitroglycerin)
Isosorbide mononitrate & Isosorbide dinitrate
Pentaerythritol Tetranitrate (PETN)
Sodium nitroprusside
PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide
Sildenafil (Viagra)
Tadalafil
Vardenafil
- Glyceryl trinitrate (commonly known as Nitroglycerin)
- Isosorbide mononitrate & Isosorbide dinitrate
- Pentaerythritol Tetranitrate (PETN)
- Sodium nitroprusside
- PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide
Sildenafil (Viagra)
Tadalafil
Vardenafil
- Sildenafil (Viagra)
- Tadalafil
- Vardenafil
- Terbutaline
- Tetrahydrocannabinol (THC) - the major active chemical in marijuana. Its mild vasodilating effects redden the eyes of cannabis smokers.
- Theobromine.
- Papaverine an alkaloid found in the opium poppy papaver somniferum
- Conjugated estrogens
# Therapeutic uses
Vasodilators are used to treat conditions such as hypertension, where the patient has an abnormally high blood pressure, as well as angina and congestive heart failure, where a maintaining a lower blood pressure reduces the patient's risk of developing other cardiac problems.
Flushing may be a physiological response to vasodilators. | Vasodilator
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A vasodilator is a drug or chemical that relaxes the smooth muscle in blood vessels, which causes them to dilate. Dilation of arterial blood vessels (mainly arterioles) lead to a decrease in blood pressure.
# Function
Vasodilation directly affects the relationship between Mean Arterial Pressure and Cardiac Output and Total Peripheral Resistance (TPR). Mathematically, cardiac output is computed by multiplying the heart rate (in beats/minute) and the stroke volume (the volume of blood ejected during systole). TPR depends on several factors including the length of the vessel, the viscosity of blood (determined by hematocrit), and the diameter of the blood vessel. The latter is the most important variable in determining resistance. An increase in either of these physiological components (cardiac output or TPR) cause a rise in the mean arterial pressure. Vasodilators work to decrease TPR and blood pressure through relaxation of smooth muscle cells in the tunica media layer of large arteries and smaller arterioles.[1]
Vasodilation occurs in superficial blood vessels of warm-blooded animals when their ambient environment is hot; this process diverts the flow of heated blood to the skin of the animal, where heat can be more easily released into the atmosphere. The opposite physiological process is vasoconstriction. These processes are naturally modulated by local paracrine agents from endothelial cells (e.g bradykinin, adenosine), as well as an organism's Autonomic Nervous System and adrenal glands, both of which secrete catecholamines such as norepinephrine and epinephrine, respectively.
# Examples and individual mechanisms
Vasodilation is a result of relaxation in smooth muscle surrounding the blood vessels. This relaxation, in turn, relies on removing the stimulus for contraction, which depends predominately on intracellular calcium ion concentrations and phosphorylation of myosin light chain (MLC). Thus, vasodilation mainly works by either by lowering intracellular calcium concentration or dephosphorylation of MLC. This includes stimulation of myosin light chain phosphatase and induction of calcium symporters and antiporters that pump calcium ions out of the intracellular compartment. This is accomplished through retuptake of ions into the sarcoplasmic reticulum via exchangers and expulsion across the plasma membrane. [2] The specific mechanisms to accomplish these effects varies from vasodilator to vasodilator.
These may be grouped as endogenous and exogenous vasodilators;
## Endogenous
## Exogenous vasodilators
- Absence of high levels of environmental noise
- Absence of high levels of illumination
- Adenocard - Adenosine agonist, primarily used as an anti-arrhythmic.
- Alpha blockers (block the vasoconstricting effect of adrenaline).
- Amyl nitrite and other nitrites are often used recreationally as a vasodilator, causing lightheadedness and a euphoric feeling.
- Atrial natriuretic peptide (ANP) - a weak vasodilator.
- Ethanol
- Histamine-inducers
Complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophil granulocytes.
- Complement proteins C3a, C4a and C5a work by triggering histamine release from mast cells and basophil granulocytes.
- Nitric oxide inducers
Glyceryl trinitrate (commonly known as Nitroglycerin)
Isosorbide mononitrate & Isosorbide dinitrate
Pentaerythritol Tetranitrate (PETN)
Sodium nitroprusside
PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide
Sildenafil (Viagra)
Tadalafil
Vardenafil
- Glyceryl trinitrate (commonly known as Nitroglycerin)
- Isosorbide mononitrate & Isosorbide dinitrate
- Pentaerythritol Tetranitrate (PETN)
- Sodium nitroprusside
- PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide
Sildenafil (Viagra)
Tadalafil
Vardenafil
- Sildenafil (Viagra)
- Tadalafil
- Vardenafil
- Terbutaline
- Tetrahydrocannabinol (THC) - the major active chemical in marijuana. Its mild vasodilating effects redden the eyes of cannabis smokers.
- Theobromine.
- Papaverine an alkaloid found in the opium poppy papaver somniferum
- Conjugated estrogens
# Therapeutic uses
Vasodilators are used to treat conditions such as hypertension, where the patient has an abnormally high blood pressure, as well as angina and congestive heart failure, where a maintaining a lower blood pressure reduces the patient's risk of developing other cardiac problems.[7]
Flushing may be a physiological response to vasodilators. | https://www.wikidoc.org/index.php/Vasodialation | |
a8fc695f57c73b68c16322dc2c4907a4aa35cb31 | wikidoc | Vemurafenib | Vemurafenib
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Vemurafenib is a kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with ] as detected by an FDA-approved test. Common adverse reactions include arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Vemurafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with ] as detected by an FDA-approved test.
- Dosage: 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vemurafenib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vemurafenib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of vemurafenib have not been established in pediatric patients younger than 18 years.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vemurafenib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vemurafenib in pediatric patients.
# Contraindications
None
# Warnings
### New Primary Malignancies
- Cutaneous squamous cell carcinoma , keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving vemurafenib compared to those in the control arm in Trial 1.
- The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the vemurafenib arm was 24% compared to < 1% in the dacarbazine arm. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving vemurafenib experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using vemurafenib included age (≥ 65 years), prior skin cancer, and chronic sun exposure.
- In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving vemurafenib compared to none of the patients receiving dacarbazine.
- Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of vemurafenib.
- Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving vemurafenib. Monitor patients receiving vemurafenib closely for signs or symptoms of new non-cutaneous SCC.
- Based on mechanism of action, vemurafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving vemurafenib closely for signs or symptoms of other malignancies.
### Tumor Promotion in BRAF Wild-Type Melanoma
- In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of ] in tumor specimens prior to initiation of vemurafenib.
### Hypersensitivity Reactions
- Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with vemurafenib. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue vemurafenib in patients who experience a severe hypersensitivity reaction.
### Dermatologic Reactions
Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving vemurafenib. Permanently discontinue vemurafenib in patients who experience a severe dermatologic reaction.
### QT Prolongation
Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.
Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of vemurafenib for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.
Withhold vemurafenib in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue vemurafenib treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).
### Hepatotoxicity
Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.
The safety and effectiveness of vemurafenib in combination with Ipilimumab have not been established. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent Ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
### Photosensitivity
Mild to severe photosensitivity can occur in patients treated with vemurafenib. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.
Institute dose modifications for intolerable Grade 2 or greater photosensitivity.
### Ophthalmologic Reactions
Uveitis, blurry vision, and photophobia can occur in patients treated with vemurafenib. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving vemurafenib compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.
### Embryo-Fetal Toxicity
vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
# Adverse Reactions
## Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with vemurafenib 960 mg orally twice daily.
TABLE 1 presents adverse reactions reported in at least 10% of patients treated with vemurafenib. The most common adverse reactions of any grade (≥ 30% in either study) in vemurafenib-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the vemurafenib arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in vemurafenib-treated patients. The median duration of study treatment was 4.2 months for vemurafenib and 0.8 months for dacarbazine in Trial 1, and 5.7 months for vemurafenib in Trial 2.
Clinically relevant adverse reactions reported in < 10% of patients treated with vemurafenib in the Phase 2 and Phase 3 studies include:
- Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis
- Musculoskeletal and connective tissue disorders: arthritis
- Nervous system disorders: peripheral neuropathy, VIIth nerve paralysis
- Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma
- Infections and infestations: folliculitis
- Eye disorders: retinal vein occlusion
- Vascular disorders: vasculitis
- Cardiac disorders: atrial fibrillation
TABLE 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of vemurafenib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation.
- Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
- Blood and lymphatic systems disorder: Neutropenia
# Drug Interactions
### Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib
Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Avoid coadministration of vemurafenib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.
### Effect of Vemurafenib on CYP1A2 Substrates
Concomitant use of vemurafenib with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as vemurafenib may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.
### Ipilimumab
Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent Ipilimumab and vemurafenib.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during vemurafenib therapy and for at least 2 months after discontinuation of vemurafenib. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vemurafenib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vemurafenib during labor and delivery.
### Nursing Mothers
It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vemurafenib in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and efficacy in pediatric patients below the age of 18 have not been established.
### Geriatic Use
Clinical studies of vemurafenib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
Based on the population pharmacokinetic analysis gender do not have a clinically important effect on the exposure of vemurafenib.
### Race
There are insufficient data to evaluate potential differences in the pharmacokinetics of vemurafenib by race.
### Renal Impairment
No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of vemurafenib has not been established in patients with severe renal impairment.
### Hepatic Impairment
No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of vemurafenib has not been established in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vemurafenib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vemurafenib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Vemurafenib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Vemurafenib and IV administrations.
# Overdosage
There is no information on overdosage of vemurafenib.
# Pharmacology
## Mechanism of Action
Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF V600E.
## Structure
Vemurafenib has the chemical name propane-1-sulfonic acid {3-pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib has the following chemical structure:
## Pharmacodynamics
In a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma, patients administered vemurafenib 960 mg orally twice daily did not experience large changes in mean QTc interval (i.e., > 20 ms) from baseline. Vemurafenib is associated with concentration-dependent QTc interval prolongation. The largest mean change from baseline in the first month of treatment occurred at 2 hours post-dose on Day 15—an increase of 12.8 ms (upper boundary of the two-sided 90% confidence interval of 14.9 ms). In the first 6 months of treatment, the largest observed mean change from baseline occurred at a pre-dose time point—an increase of 15.1 ms (upper boundary of the two-sided 90% confidence interval of 17.7 ms).
## Pharmacokinetics
The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. At steady-state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.
The bioavailability of vemurafenib has not been determined. The median Tmax was approximately 3 hours following multiple doses.
The mean (± SD) Cmax and AUC0-12 were 62 ± 17 µg/mL and 601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.4, with steady-state achieved at approximately 15 to 22 days.
In clinical trials, vemurafenib was administered without regard to food. A food effect study has demonstrated that a single dose of vemurafenib administered with a high-fat meal increased AUC by approximately 5-fold, increased Cmax by 2.5-fold, and delayed Tmax by approximately 4 hours as compared to the fasted state.
QTc prolongation may occur with increased exposures as vemurafenib is associated with concentration-dependent QTc interval prolongation.
Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution is estimated to be 106 L (with 66% inter-patient variability).
Following oral administration of 960 mg of 14C-vemurafenib, mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma over 48 hours, respectively.
Following oral administration of 960 mg of 14C-vemurafenib, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance is estimated to be 31 L/day (with 32% inter-patient variability). The median elimination half-life estimate for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).
## Nonclinical Toxicology
There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. vemurafenib increased the development of cutaneous squamous cell carcinomas in patients in clinical trials.
Vemurafenib did not cause genetic damage when tested in in vitro assays (bacterial mutation , human lymphocyte chromosome aberration) or in the in vivo rat bone marrow micronucleus test.
Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose dependent acceleration of the growth of the implanted tumors.
# Clinical Studies
### Treatment Naive Patients
Trial 1, an international, open-label, randomized controlled trial, equally allocated 675 patients with treatment-naive, BRAF V600E mutation-positive unresectable or metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, to receive vemurafenib 960 mg by mouth twice daily (n=337) or dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks (n=338). Randomization stratification factors were disease stage, lactate dehydrogenase (LDH), ECOG performance status, and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.
Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%).
Trial 1 demonstrated statistically significant increases in overall survival and progression-free survival in the vemurafenib arm compared to the dacarbazine control arm. TABLE 3 and FIGURE 1 summarize the efficacy results.
The confirmed, investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in the vemurafenib arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the vemurafenib arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm.
### Patients Who Received Prior Systemic Therapy
In a single-arm, multicenter, multinational trial (Trial 2), 132 patients with BRAF V600E mutation-positive metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, who had received at least one prior systemic therapy, received vemurafenib 960 mg by mouth twice daily. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 to 11.3).
The confirmed best overall response rate as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response by IRC was 6.5 months (95% CI: 5.6, not reached).
### Patients with Wild-Type BRAF Melanoma
Vemurafenib has not been studied in patients with wild-type BRAF melanoma.
# How Supplied
Vemurafenib is supplied as 240 mg film-coated tablets:
- NDC 50242-090-01 single bottle of 120 count
- NDC 50242-090-02 single bottle of 112 count
## Storage
Store at room temperature 20°C–25°C (68°F–77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Health care providers should advise patients of the potential benefits and risks of vemurafenib and instruct their patients to read the MEDICATION GUIDE before starting vemurafenib therapy. Inform patients of the following:
- Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with vemurafenib is indicated.
- vemurafenib increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin.
- Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with vemurafenib. Advise patients to stop taking vemurafenib and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity.
- Severe dermatologic reactions can occur in patients receiving vemurafenib. Advise patients to stop taking vemurafenib and to contact their health care provider for severe dermatologic reactions.
- Vemurafenib can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during vemurafenib treatment .
- Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib. Advise patients of the importance of laboratory monitoring of their liver during vemurafenib treatment and to contact their health care provider for relevant symptoms.
- Vemurafenib can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.
- Ophthalmologic reactions can occur in patients treated with vemurafenib. Advise patients to contact their health care provider immediately for ophthalmologic symptoms.
- Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during vemurafenib therapy and for at least 2 months after discontinuation of vemurafenib. Advise patients to contact their health care provider immediately if they become pregnant.
# Precautions with Alcohol
Alcohol-Vemurafenib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zelboraf
# Look-Alike Drug Names
There is limited information regarding Vemurafenib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vemurafenib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2];Aparna Vuppala, M.B.B.S. [3]
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# Overview
Vemurafenib is a kinase inhibitor that is FDA approved for the treatment of patients with unresectable or metastatic melanoma with [[BRAF|BRAF V600E mutation]] as detected by an FDA-approved test. Common adverse reactions include arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Vemurafenib is indicated for the treatment of patients with unresectable or metastatic melanoma with [[BRAF|BRAF V600E mutation]] as detected by an FDA-approved test.
- Dosage: 960 mg (four 240 mg tablets) orally every 12 hours with or without a meal.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vemurafenib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vemurafenib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy of vemurafenib have not been established in pediatric patients younger than 18 years.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vemurafenib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vemurafenib in pediatric patients.
# Contraindications
None
# Warnings
### New Primary Malignancies
- Cutaneous squamous cell carcinoma , keratoacanthoma, and melanoma occurred at a higher incidence in patients receiving vemurafenib compared to those in the control arm in Trial 1.
- The incidence of cutaneous squamous cell carcinomas (cuSCC) and keratoacanthomas in the vemurafenib arm was 24% compared to < 1% in the dacarbazine arm. The median time to the first appearance of cuSCC was 7 to 8 weeks; approximately 33% of patients who developed a cuSCC while receiving vemurafenib experienced at least one additional occurrence with median time between occurrences of 6 weeks. Potential risk factors associated with cuSCC observed in clinical studies using vemurafenib included age (≥ 65 years), prior skin cancer, and chronic sun exposure.
- In Trial 1, new primary malignant melanoma occurred in 2.1% (7/336) of patients receiving vemurafenib compared to none of the patients receiving dacarbazine.
- Perform dermatologic evaluations prior to initiation of therapy and every 2 months while on therapy. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Consider dermatologic monitoring for 6 months following discontinuation of vemurafenib.
- Non-cutaneous squamous cell carcinomas (SCC) of the head and neck can occur in patients receiving vemurafenib. Monitor patients receiving vemurafenib closely for signs or symptoms of new non-cutaneous SCC.
- Based on mechanism of action, vemurafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving vemurafenib closely for signs or symptoms of other malignancies.
### Tumor Promotion in BRAF Wild-Type Melanoma
- In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells that are exposed to BRAF inhibitors. Confirm evidence of [[BRAF|BRAF V600E mutation]] in tumor specimens prior to initiation of vemurafenib.
### Hypersensitivity Reactions
- Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with vemurafenib. Severe hypersensitivity reactions included generalized rash and erythema, hypotension, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Permanently discontinue vemurafenib in patients who experience a severe hypersensitivity reaction.
### Dermatologic Reactions
Severe dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, can occur in patients receiving vemurafenib. Permanently discontinue vemurafenib in patients who experience a severe dermatologic reaction.
### QT Prolongation
Concentration-dependent QT prolongation occurred in an uncontrolled, open-label QT sub-study in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. QT prolongation may lead to an increased risk of ventricular arrhythmias, including Torsade de Pointes.
Do not start treatment in patients with uncorrectable electrolyte abnormalities, QTc > 500 ms, or long QT syndrome, or in patients who are taking medicinal products known to prolong the QT interval. Prior to and following treatment initiation or after dose modification of vemurafenib for QTc prolongation, evaluate ECG and electrolytes (including potassium, magnesium, and calcium) after 15 days, monthly during the first 3 months, and then every 3 months thereafter or more often as clinically indicated.
Withhold vemurafenib in patients who develop QTc > 500 ms (Grade 3). Upon recovery to QTc ≤ 500 ms (Grade ≤ 2), restart at a reduced dose. Permanently discontinue vemurafenib treatment if the QTc interval remains > 500 ms and increased > 60 ms from pre-treatment values after controlling cardiac risk factors for QT prolongation (e.g., electrolyte abnormalities, congestive heart failure, and bradyarrhythmias).
### Hepatotoxicity
Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib. Monitor transaminases, alkaline phosphatase, and bilirubin before initiation of treatment and monthly during treatment, or as clinically indicated. Manage laboratory abnormalities with dose reduction, treatment interruption, or treatment discontinuation.
The safety and effectiveness of vemurafenib in combination with Ipilimumab have not been established. In a dose-finding trial, Grade 3 increases in transaminases and bilirubin occurred in a majority of patients who received concurrent Ipilimumab (3 mg/kg) and vemurafenib (960 mg BID or 720 mg BID).
### Photosensitivity
Mild to severe photosensitivity can occur in patients treated with vemurafenib. Advise patients to avoid sun exposure, wear protective clothing and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors.
Institute dose modifications for intolerable Grade 2 or greater photosensitivity.
### Ophthalmologic Reactions
Uveitis, blurry vision, and photophobia can occur in patients treated with vemurafenib. In Trial 1, uveitis, including iritis, occurred in 2.1% (7/336) of patients receiving vemurafenib compared to no patients in the dacarbazine arm. Treatment with steroid and mydriatic ophthalmic drops may be required to manage uveitis. Monitor patients for signs and symptoms of uveitis.
### Embryo-Fetal Toxicity
vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
# Adverse Reactions
## Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
This section describes adverse drug reactions (ADRs) identified from analyses of Trial 1 and Trial 2. Trial 1 randomized (1:1) 675 treatment-naive patients with unresectable or metastatic melanoma to receive vemurafenib 960 mg orally twice daily or dacarbazine 1000 mg/m2 intravenously every 3 weeks. In Trial 2, 132 patients with metastatic melanoma and failure of at least one prior systemic therapy received treatment with vemurafenib 960 mg orally twice daily.
TABLE 1 presents adverse reactions reported in at least 10% of patients treated with vemurafenib. The most common adverse reactions of any grade (≥ 30% in either study) in vemurafenib-treated patients were arthralgia, rash, alopecia, fatigue, photosensitivity reaction, nausea, pruritus, and skin papilloma. The most common (≥ 5%) Grade 3 adverse reactions were cuSCC and rash. The incidence of Grade 4 adverse reactions was ≤ 4% in both studies.
The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 7% for the vemurafenib arm and 4% for the dacarbazine arm. In Trial 2, the incidence of adverse events resulting in permanent discontinuation of study medication was 3% in vemurafenib-treated patients. The median duration of study treatment was 4.2 months for vemurafenib and 0.8 months for dacarbazine in Trial 1, and 5.7 months for vemurafenib in Trial 2.
Clinically relevant adverse reactions reported in < 10% of patients treated with vemurafenib in the Phase 2 and Phase 3 studies include:
- Skin and subcutaneous tissue disorders: palmar-plantar erythrodysesthesia syndrome, keratosis pilaris, panniculitis, erythema nodosum, Stevens-Johnson syndrome, toxic epidermal necrolysis
- Musculoskeletal and connective tissue disorders: arthritis
- Nervous system disorders: peripheral neuropathy, VIIth nerve paralysis
- Neoplasms benign, malignant and unspecified (includes cysts and polyps): basal cell carcinoma, oropharyngeal squamous cell carcinoma
- Infections and infestations: folliculitis
- Eye disorders: retinal vein occlusion
- Vascular disorders: vasculitis
- Cardiac disorders: atrial fibrillation
TABLE 2 shows the incidence of worsening liver laboratory abnormalities in Trial 1 summarized as the proportion of patients who experienced a shift from baseline to Grade 3 or 4.
## Postmarketing Experience
The following adverse reactions have been identified during postapproval use of vemurafenib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Progression of a pre-existing chronic myelomonocytic leukemia with NRAS mutation.
- Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
- Blood and lymphatic systems disorder: Neutropenia
# Drug Interactions
### Effect of Strong CYP3A4 Inhibitors or Inducers on Vemurafenib
Vemurafenib is a substrate of CYP3A4 based on in vitro data; therefore, coadministration of strong CYP3A4 inhibitors or inducers may alter vemurafenib concentrations. Avoid coadministration of vemurafenib with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or strong inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), and replace these drugs with alternative drugs when possible.
### Effect of Vemurafenib on CYP1A2 Substrates
Concomitant use of vemurafenib with drugs with a narrow therapeutic window that are predominantly metabolized by CYP1A2 is not recommended as vemurafenib may increase concentrations of CYP1A2 substrates. If coadministration cannot be avoided, monitor closely for toxicities and consider a dose reduction of concomitant CYP1A2 substrates.
### Ipilimumab
Increases in transaminases and bilirubin occurred in a majority of patients who received concurrent Ipilimumab and vemurafenib.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action.
Vemurafenib revealed no evidence of teratogenicity in rat embryo/fetuses at doses up to 250 mg/kg/day (approximately 1.3 times the human clinical exposure based on AUC) or rabbit embryo/fetuses at doses up to 450 mg/kg/day (approximately 0.6 times the human clinical exposure based on AUC). Fetal drug levels were 3–5% of maternal levels, indicating that vemurafenib has the potential to be transmitted from the mother to the developing fetus. There are no adequate and well controlled studies in pregnant women. Women of childbearing potential and men should be advised to use appropriate contraceptive measures during vemurafenib therapy and for at least 2 months after discontinuation of vemurafenib. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vemurafenib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vemurafenib during labor and delivery.
### Nursing Mothers
It is not known whether vemurafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vemurafenib in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and efficacy in pediatric patients below the age of 18 have not been established.
### Geriatic Use
Clinical studies of vemurafenib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
Based on the population pharmacokinetic analysis gender do not have a clinically important effect on the exposure of vemurafenib.
### Race
There are insufficient data to evaluate potential differences in the pharmacokinetics of vemurafenib by race.
### Renal Impairment
No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate renal impairment based on a population pharmacokinetic analysis. The appropriate dose of vemurafenib has not been established in patients with severe renal impairment.
### Hepatic Impairment
No formal clinical study has been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of vemurafenib. No dose adjustment is recommended for patients with mild and moderate hepatic impairment based on a population pharmacokinetic analysis. The appropriate dose of vemurafenib has not been established in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vemurafenib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vemurafenib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Vemurafenib Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Vemurafenib and IV administrations.
# Overdosage
There is no information on overdosage of vemurafenib.
# Pharmacology
Template:Infobox drug mechanism
## Mechanism of Action
Vemurafenib is a low molecular weight, orally available inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. Vemurafenib also inhibits other kinases in vitro such as CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, and FGR at similar concentrations. Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Vemurafenib has anti-tumor effects in cellular and animal models of melanomas with mutated BRAF V600E.
## Structure
Vemurafenib has the chemical name propane-1-sulfonic acid {3-[5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide. It has the molecular formula C23H18ClF2N3O3S and a molecular weight of 489.9. Vemurafenib has the following chemical structure:
## Pharmacodynamics
In a multi-center, open-label, single-arm study in 132 patients with BRAF V600E mutation-positive metastatic melanoma, patients administered vemurafenib 960 mg orally twice daily did not experience large changes in mean QTc interval (i.e., > 20 ms) from baseline. Vemurafenib is associated with concentration-dependent QTc interval prolongation. The largest mean change from baseline in the first month of treatment occurred at 2 hours post-dose on Day 15—an increase of 12.8 ms (upper boundary of the two-sided 90% confidence interval of 14.9 ms). In the first 6 months of treatment, the largest observed mean change from baseline occurred at a pre-dose time point—an increase of 15.1 ms (upper boundary of the two-sided 90% confidence interval of 17.7 ms).
## Pharmacokinetics
The pharmacokinetics of vemurafenib were determined in patients with BRAF mutation-positive metastatic melanoma following 15 days of 960 mg twice daily with dosing approximately 12 hours apart. The population pharmacokinetic analysis pooled data from 458 patients. At steady-state, vemurafenib exhibits linear pharmacokinetics within the 240 mg to 960 mg dose range.
The bioavailability of vemurafenib has not been determined. The median Tmax was approximately 3 hours following multiple doses.
The mean (± SD) Cmax and AUC0-12 were 62 ± 17 µg/mL and 601 ± 170 µg*h/mL, respectively. The median accumulation ratio estimate from the population pharmacokinetic analysis for the twice daily regimen is 7.4, with steady-state achieved at approximately 15 to 22 days.
In clinical trials, vemurafenib was administered without regard to food. A food effect study has demonstrated that a single dose of vemurafenib administered with a high-fat meal increased AUC by approximately 5-fold, increased Cmax by 2.5-fold, and delayed Tmax by approximately 4 hours as compared to the fasted state.
QTc prolongation may occur with increased exposures as vemurafenib is associated with concentration-dependent QTc interval prolongation.
Vemurafenib is highly bound (> 99%) to human albumin and alpha-1 acid glycoprotein plasma proteins. The population apparent volume of distribution is estimated to be 106 L (with 66% inter-patient variability).
Following oral administration of 960 mg of 14C-vemurafenib, mean data showed that vemurafenib and its metabolites represented 95% and 5% of the components in plasma over 48 hours, respectively.
Following oral administration of 960 mg of 14C-vemurafenib, approximately 94% of the radioactive dose was recovered in feces and approximately 1% was recovered in the urine. The population apparent clearance is estimated to be 31 L/day (with 32% inter-patient variability). The median elimination half-life estimate for vemurafenib is 57 hours (the 5th and 95th percentile range is 30 to 120 hours).
## Nonclinical Toxicology
There have been no formal studies conducted assessing the carcinogenic potential of vemurafenib. vemurafenib increased the development of cutaneous squamous cell carcinomas in patients in clinical trials.
Vemurafenib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) or in the in vivo rat bone marrow micronucleus test.
Consistent with the increased incidence of cutaneous squamous cell carcinomas in patients treated with vemurafenib, the treatment of mice implanted with human cuSCC cells with vemurafenib caused a dose dependent acceleration of the growth of the implanted tumors.
# Clinical Studies
### Treatment Naive Patients
Trial 1, an international, open-label, randomized controlled trial, equally allocated 675 patients with treatment-naive, BRAF V600E mutation-positive unresectable or metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, to receive vemurafenib 960 mg by mouth twice daily (n=337) or dacarbazine 1000 mg/m2 intravenously on Day 1 every 3 weeks (n=338). Randomization stratification factors were disease stage, lactate dehydrogenase (LDH), ECOG performance status, and geographic region. Treatment continued until disease progression, unacceptable toxicity, and/or consent withdrawal. The major efficacy outcome measures of the trial were overall survival (OS) and investigator-assessed progression-free survival (PFS). Other outcome measures included confirmed investigator-assessed best overall response rate.
Baseline characteristics were balanced between treatment groups. Most patients were male (56%) and caucasian (99%), the median age was 54 years (24% were ≥ 65 years), all patients had ECOG performance status of 0 or 1, and the majority of patients had metastatic disease (95%).
Trial 1 demonstrated statistically significant increases in overall survival and progression-free survival in the vemurafenib arm compared to the dacarbazine control arm. TABLE 3 and FIGURE 1 summarize the efficacy results.
The confirmed, investigator-assessed best overall response rate was 48.4% (95% CI: 41.6%, 55.2%) in the vemurafenib arm compared to 5.5% (95% CI: 2.8%, 9.3%) in the dacarbazine arm. There were 2 complete responses (0.9%) and 104 partial responses (47.4%) in the vemurafenib arm and all 12 responses were partial responses (5.5%) in the dacarbazine arm.
### Patients Who Received Prior Systemic Therapy
In a single-arm, multicenter, multinational trial (Trial 2), 132 patients with BRAF V600E mutation-positive metastatic melanoma, as detected by the cobas® 4800 BRAF V600 Mutation Test, who had received at least one prior systemic therapy, received vemurafenib 960 mg by mouth twice daily. The median age was 52 years with 19% of patients being older than 65 years. The majority of patients were male (61%) and Caucasian (99%). Forty-nine percent of patients received ≥ 2 prior therapies. The median duration of follow-up was 6.87 months (range, 0.6 to 11.3).
The confirmed best overall response rate as assessed by an independent review committee (IRC) was 52% (95% CI: 43%, 61%). There were 3 complete responses (2.3%) and 66 partial responses (50.0%). The median time to response was 1.4 months with 75% of responses occurring by month 1.6 of treatment. The median duration of response by IRC was 6.5 months (95% CI: 5.6, not reached).
### Patients with Wild-Type BRAF Melanoma
Vemurafenib has not been studied in patients with wild-type BRAF melanoma.
# How Supplied
Vemurafenib is supplied as 240 mg film-coated tablets:
- NDC 50242-090-01 single bottle of 120 count
- NDC 50242-090-02 single bottle of 112 count
## Storage
Store at room temperature 20°C–25°C (68°F–77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Health care providers should advise patients of the potential benefits and risks of vemurafenib and instruct their patients to read the MEDICATION GUIDE before starting vemurafenib therapy. Inform patients of the following:
- Evidence of BRAF V600E mutation in the tumor specimen with an FDA approved test is necessary to identify patients for whom treatment with vemurafenib is indicated.
- vemurafenib increases the risk of developing new primary cutaneous malignancies. Advise patients of the importance of contacting their health care provider immediately for any changes in their skin.
- Anaphylaxis and other serious hypersensitivity reactions can occur during treatment and upon re-initiation of treatment with vemurafenib. Advise patients to stop taking vemurafenib and to seek immediate medical attention for symptoms of anaphylaxis or hypersensitivity.
- Severe dermatologic reactions can occur in patients receiving vemurafenib. Advise patients to stop taking vemurafenib and to contact their health care provider for severe dermatologic reactions.
- Vemurafenib can prolong QT interval, which may result in ventricular arrhythmias. Advise patients of the importance of monitoring of their electrolytes and the electrical activity of their heart (via an ECG) during vemurafenib treatment .
- Liver injury leading to functional hepatic impairment, including coagulopathy or other organ dysfunction, can occur with vemurafenib. Advise patients of the importance of laboratory monitoring of their liver during vemurafenib treatment and to contact their health care provider for relevant symptoms.
- Vemurafenib can cause mild to severe photosensitivity. Advise patients to avoid sun exposure, wear protective clothing, and use a broad spectrum UVA/UVB sunscreen and lip balm (SPF ≥ 30) when outdoors to help protect against sunburn.
- Ophthalmologic reactions can occur in patients treated with vemurafenib. Advise patients to contact their health care provider immediately for ophthalmologic symptoms.
- Vemurafenib can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Advise women of childbearing potential and men to use appropriate contraceptive measures during vemurafenib therapy and for at least 2 months after discontinuation of vemurafenib. Advise patients to contact their health care provider immediately if they become pregnant.
# Precautions with Alcohol
Alcohol-Vemurafenib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Zelboraf [1]
# Look-Alike Drug Names
There is limited information regarding Vemurafenib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Vemurafenib | |
16eb9fd863c3e22b81b90f47ee5a071fb5b657d5 | wikidoc | Vernakalant | Vernakalant
# Overview
Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation has been bought for further development by Merck in April 2009.
On December 11, 2007, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted to recommend the approval of vernakalant, but in August 2008 the FDA judged that additional information was necessary for approval.
The drug was approved in Europe on September 1, 2010.
An oral formulation underwent Phase II clinical trials between 2005 and 2008.
# Mechanism of action
Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant.
The drug also blocks atrial sodium channels. | Vernakalant
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Vernakalant (INN; codenamed RSD1235, proposed tradenames Kynapid and Brinavess) is an investigational drug under regulatory review for the acute conversion of atrial fibrillation. It was initially developed by Cardiome Pharma, and the intravenous formulation has been bought for further development by Merck in April 2009.[1]
On December 11, 2007, the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted to recommend the approval of vernakalant,[2] but in August 2008 the FDA judged that additional information was necessary for approval.[1]
The drug was approved in Europe on September 1, 2010.[3]
An oral formulation underwent Phase II clinical trials between 2005 and 2008.[4][5]
# Mechanism of action
Like other class III antiarrhythmics, vernakalant blocks atrial potassium channels, thereby prolonging repolarization. It differs from typical class III agents by blocking a certain type of potassium channel, the cardiac transient outward potassium current, with increased potency as the heart rate increases. This means that it is more effective at high heart rates, while other class III agents tend to lose effectiveness under these circumstances. It also slightly blocks the hERG potassium channel, leading to a prolonged QT interval. This may theoretically increase the risk of ventricular tachycardia, though this does not seem to be clinically relevant.[6]
The drug also blocks atrial sodium channels.[6] | https://www.wikidoc.org/index.php/Vernakalant | |
c54676c76182665064e226fe91511b3e9ca77b40 | wikidoc | Verteporfin | Verteporfin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Verteporfin is a photosensitizing agent that is FDA approved for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. Common adverse reactions include injection site reaction, blurred vision, photopsia, reduced visual acuity, visual field defect.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Visudyne® (verteporfin for injection) therapy is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.
- There is insufficient evidence to indicate Visudyne for the treatment of predominantly occult subfoveal choroidal neovascularization.
- A course of Visudyne® (verteporfin for injection) therapy is a two-step process requiring administration of both drug and light.
- The first step is the intravenous infusion of Visudyne. The second step is the activation of Visudyne with light from a nonthermal diode laser.
- The physician should reevaluate the patient every 3 months and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.
- Lesion Size Determination
- The greatest linear dimension (GLD) of the lesion is estimated by fluorescein angiography and color fundus photography. All classic and occult CNV, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium should be included for this measurement. Fundus cameras with magnification within the range of 2.4-2.6X are recommended. The GLD of the lesion on the fluorescein angiogram must be corrected for the magnification of the fundus camera to obtain the GLD of the lesion on the retina.
- Spot Size Determination
- The treatment spot size should be 1000 microns larger than the GLD of the lesion on the retina to allow a 500 micron border, ensuring full coverage of the lesion. The maximum spot size used in the clinical trials was 6400 microns.
- The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc, even if this will result in lack of photoactivation of CNV within 200 microns of the optic nerve.
- Visudyne® Administration
- Reconstitute each vial of Visudyne with 7 mL of sterile Water for Injection to provide 7.5 mL containing 2 mg/mL. Reconstituted Visudyne must be protected from light and used within 4 hours. It is recommended that reconstituted Visudyne be inspected visually for particulate matter and discoloration prior to administration. Reconstituted Visudyne is an opaque dark green solution. Visudyne may precipitate in saline solutions. Do not use normal saline or other parenteral solutions, except 5% Dextrose for Injection, for dilution of the reconstituted Visudyne. Do not mix Visudyne in the same solution with other drugs.
- The volume of reconstituted Visudyne required to achieve the desired dose of 6 mg/m2 body surface area is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total infusion volume of 30 mL. After dilution, protect from light and use within a maximum of 4 hours. The full infusion volume is administered intravenously over 10 minutes at a rate of 3 mL/minute, using an appropriate syringe pump and in-line filter. The clinical studies were conducted using a standard infusion line filter of 1.2 microns.
- Precautions should be taken to prevent extravasation at the injection site. If extravasation occurs, protect the site from light.
- Light Administration
- Initiate 689 nm wavelength laser light delivery to the patient 15 minutes after the start of the 10-minute infusion with Visudyne.
- Photoactivation of Visudyne is controlled by the total light dose delivered. In the treatment of choroidal neovascularization, the recommended light dose is 50 J/cm2 of neovascular lesion administered at an intensity of 600 mW/cm2. This dose is administered over 83 seconds.
- Light dose, light intensity, ophthalmic lens magnification factor and zoom lens setting are important parameters for the appropriate delivery of light to the predetermined treatment spot. Follow the laser system manuals for procedure set up and operation.
- The laser system must deliver a stable power output at a wavelength of 689±3 nm. Light is delivered to the retina as a single circular spot via a fiber optic and a slit lamp, using a suitable ophthalmic magnification lens.
- The following laser systems have been tested for compatibility with Visudyne and are approved for delivery of a stable power output at a wavelength of 689±3 nm:
- Coherent Opal Photoactivator laser console and modified Coherent LaserLink adapter, manufactured by Lumenis, Inc., 2400 Condensa Street, Santa Clara, CA 95051-0901,
- Zeiss VISULAS 690s laser and VISULINK® PDT adapter manufactured by Carl Zeiss Meditec Inc., 5160 Hacienda Drive, Dublin, CA 94568,
- Ceralas™ I laser system and Ceralink™ Slit Lamp Adapter manufactured by Biolitec Inc., 515 Shaker Road, East Longmeadow, MA 01028,
- Quantel Activis laser console and the ZSL30 ACT™, ZSL120 ACT™ and HSBMBQ ACT™ slit lamp adapters distributed by Quantel Medical, 601 Haggerty Lane, Bozeman, MT 59715.
- Concurrent Bilateral Treatment
- The controlled trials only allowed treatment of one eye per patient. In patients who present with eligible lesions in both eyes, physicians should evaluate the potential benefits and risks of treating both eyes concurrently. If the patient has already received previous Visudyne therapy in one eye with an acceptable safety profile, both eyes can be treated concurrently after a single administration of Visudyne. The more aggressive lesion should be treated first, at 15 minutes after the start of infusion. Immediately at the end of light application to the first eye, the laser settings should be adjusted to introduce the treatment parameters for the second eye, with the same light dose and intensity as for the first eye, starting no later than 20 minutes from the start of infusion.
- In patients who present for the first time with eligible lesions in both eyes without prior Visudyne therapy, it is prudent to treat only one eye (the most aggressive lesion) at the first course. One week after the first course, if no significant safety issues are identified, the second eye can be treated using the same treatment regimen after a second Visudyne infusion. Approximately 3 months later, both eyes can be evaluated and concurrent treatment following a new Visudyne infusion can be started if both lesions still show evidence of leakage.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Verteporfin in adult patients.
### Non–Guideline-Supported Use
- Intravenous verteporfin/laser therapy efficacious in nonmelanoma/metastatic carcinomas - 0.25 to 0.5 mg/kg (50 to 150 J/cm(2) laser light.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Verteporfin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Verteporfin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Verteporfin in pediatric patients.
# Contraindications
- Visudyne® (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation.
# Warnings
- Following injection with Visudyne® (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. In the event of extravasation during infusion, the extravasation area must be thoroughly protected from direct light until the swelling and discoloration have faded in order to prevent the occurrence of a local burn which could be severe. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light.
- Patients who experience severe decrease of vision of ≥4 lines within 1 week after treatment should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician.
- Use of incompatible lasers that do not provide the required characteristics of light for the photoactivation of Visudyne could result in incomplete treatment due to partial photoactivation of Visudyne , overtreatment due to overactivation of Visudyne , or damage to surrounding normal tissue.
### Precautions
- Standard precautions should be taken during infusion of Visudyne® (verteporfin for injection) to avoid extravasation. Examples of standard precautions include, but are not limited to:
- Free-flowing intravenous (IV) line should be established before starting Visudyne infusion and the line should be carefully monitored.
- Due to the possible fragility of vein walls of some elderly patients, it is strongly recommended that the largest arm vein possible, preferably antecutibal, be used for injection.
- Small veins in the back of the hand should be avoided.
- Extravasation of Visudyne, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling or discoloration at the injection site.
- If extravasation does occur, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of a local burn, which could be severe. Cold compresses should be applied to the injection site. Oral medications for pain relief may be administered.
- Visudyne therapy should be considered carefully in patients with moderate to severe hepatic impairment or biliary obstruction since there is no clinical experience with verteporfin in such patients.
- There is no clinical data related to the use of Visudyne in anesthetized patients. At a >10-fold higher dose given by bolus injection to sedated or anesthetized pigs, verteporfin caused severe hemodynamic effects, including death, probably as a result of complement activation. These effects were diminished or abolished by pretreatment with antihistamine and they were not seen in conscious nonsedated pigs. VISUDYNE resulted in a concentration-dependent increase in complement activation in human blood in vitro. At 10 µg/mL (approximately 5 times the expected plasma concentration in human patients), there was mild to moderate complement activation. At ≥100 µg/mL, there was significant complement activation. Signs (chest pain, syncope, dyspnea, and flushing) consistent with complement activation have been observed in <1% of patients administered Visudyne. Patients should be supervised during Visudyne infusion.
# Adverse Reactions
## Clinical Trials Experience
- Severe chest pain, vasovagal and hypersensitivity reactions have been reported. Vasovagal and hypersensitivity reactions on rare occasions can be severe. These reactions may include syncope, sweating, dizziness, rash, dyspnea, flushing and changes in blood pressure and heart rate. General symptoms can include headache, malaise, urticaria, and pruritus.
- The most frequently reported adverse events to Visudyne® (verteporfin for injection) are injection site reactions (including pain, edema, inflammation, extravasation, rashes, hemorrhage and discoloration) and visual disturbances (including blurred vision, flashes of light, decreased visual acuity and visual field defects, including scotoma). These events occurred in approximately 10%-30% of patients. The following events, listed by Body System, were reported more frequently with Visudyne therapy than with placebo therapy and occurred in 1%-10% of patients:
- Ocular Treatment Site: Blepharitis, cataracts, conjunctivitis/conjunctival injection, dry eyes, ocular itching, severe vision decrease with or without subretinal/retinal or vitreous hemorrhage
Asthenia, fever, flu syndrome, infusion related pain primarily presenting as back pain, photosensitivity reactions
Atrial fibrillation, hypertension, peripheral vascular disorder, varicose veins
Eczema
Constipation, gastrointestinal cancers, nausea
Anemia, white blood cell count decreased, white blood cell count increased
Elevated liver function tests
Albuminuria, creatinine increased
Arthralgia, arthrosis, myasthenia
Hypesthesia, sleep disorder, vertigo
Cough, pharyngitis, pneumonia
Cataracts, decreased hearing, diplopia, lacrimation disorder
Prostatic disorder
- Severe vision decrease, equivalent of ≥4 lines, within 7 days after treatment has been reported in 1%-5% of patients. Partial recovery of vision was observed in some patients. Photosensitivity reactions usually occurred in the form of skin sunburn following exposure to sunlight. The higher incidence of back pain in the Visudyne group occurred primarily during infusion.
## Postmarketing Experience
- The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of Visudyne in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Visudyne, or a combination of these factors:
- Ocular Treatment Site: Retinal detachment (nonrhegmatogenous), retinal or choroidal vessel nonperfusion, retinal pigment epithelial tear
- Non-ocular Events: Chest pain and other musculoskeletal pain during infusion
# Drug Interactions
- Drug interaction studies in humans have not been conducted with Visudyne.
- Verteporfin is rapidly eliminated by the liver, mainly as unchanged drug. Metabolism is limited and occurs by liver and plasma esterases. Microsomal cytochrome P450 does not appear to play a role in verteporfin metabolism.
- Based on the mechanism of action of verteporfin, many drugs used concomitantly could influence the effect of Visudyne therapy. Possible examples include the following:
- Calcium channel blockers, polymyxin B or radiation therapy could enhance the rate of Visudyne uptake by the vascular endothelium. Other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics and griseofulvin) could increase the potential for skin photosensitivity reactions. Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, β-carotene, ethanol, formate and mannitol, would be expected to decrease Visudyne activity. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could also decrease the efficacy of Visudyne therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Rat fetuses of dams administered verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis (approximately 40-fold human exposure at 6 mg/m2 based on AUCinf in female rats) exhibited an increase in the incidence of anophthalmia/microphthalmia. Rat fetuses of dams administered 25 mg/kg/day (approximately 125 fold the human exposure at 6 mg/m2 based on AUCinf in female rats) had an increased incidence of wavy ribs and anophthalmia/microphthalmia.
- In pregnant rabbits, a decrease in body weight gain and food consumption was observed in animals that received verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis. The no observed adverse effect level (NOAEL) for maternal toxicity was 3 mg/kg/day (approximately 7-fold human exposure at 6 mg/m2 based on body surface area). There were no teratogenic effects observed in rabbits at doses up to 10 mg/kg/day.
- There are no adequate and well-controlled studies in pregnant women. Visudyne should be used during pregnancy only if the benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Verteporfin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Verteporfin during labor and delivery.
### Nursing Mothers
- Verteporfin and its diacid metabolite have been found in the breast milk of one woman after a 6 mg/m2 infusion. The verteporfin breast milk levels were up to 66% of the corresponding plasma levels and declined below the limit of quantification (2 ng/mL) within 24 hours. The diacid metabolite had lower peak concentrations but persisted up to at least 48 hours.
- Because of the potential for serious adverse reactions in nursing infants from Visudyne, a decision should be made whether to discontinue nursing or postpone treatment, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Approximately 90% of the patients treated with Visudyne in the clinical efficacy trials were over the age of 65. A reduced treatment effect was seen with increasing age.
### Gender
There is no FDA guidance on the use of Verteporfin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Verteporfin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Verteporfin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Verteporfin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Verteporfin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Verteporfin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Verteporfin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Verteporfin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdose of drug and/or light in the treated eye may result in nonperfusion of normal retinal vessels with the possibility of severe decrease in vision that could be permanent. An overdose of drug will also result in the prolongation of the period during which the patient remains photosensitive to bright light. In such cases, it is recommended to extend the photosensitivity precautions for a time proportional to the overdose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Verteporfin in the drug label.
# Pharmacology
## Mechanism of Action
- Visudyne® (verteporfin for injection) therapy is a two-stage process requiring administration of both verteporfin for injection and nonthermal red light.
- Verteporfin is transported in the plasma primarily by lipoproteins. Once verteporfin is activated by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. Therefore, there may be collateral damage to retinal structures following photoactivation including the retinal pigmented epithelium and outer nuclear layer of the retina. The temporary occlusion of choroidal neovascularization (CNV) following Visudyne therapy has been confirmed in humans by fluorescein angiography.
## Structure
- Visudyne® (verteporfin for injection) is a light activated drug used in photodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:
- The chemical names for the verteporfin regioisomers are:
- 9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzoporphine-9,13-dipropanoate
- The molecular formula is C41H42N4O8 with a molecular weight of approximately 718.8.
- Each mL of reconstituted VISUDYNE contains:
- ACTIVE: Verteporfin, 2 mg
- INACTIVES: ascorbyl palmitate, butylated hydroxytoluene, dimyristoyl phosphatidylcholine, egg phosphatidylglycerol and lactose
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Verteporfin in the drug label.
## Pharmacokinetics
- Following intravenous infusion, verteporfin exhibits a bi-exponential elimination with a terminal elimination half-life of approximately 5-6 hours. The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2. At the intended dose, pharmacokinetic parameters are not significantly affected by gender.
- Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent liver enzyme systems (including the cytochrome P450 isozymes) do not appear to play a role in the metabolism of verteporfin. Elimination is by the fecal route, with less than 0.01% of the dose recovered in urine.
- In a study of patients with mild hepatic insufficiency (defined as having two abnormal hepatic function tests at enrollment), AUC and Cmax were not significantly different from the control group; half-life, however, was significantly increased by approximately 20%.
## Nonclinical Toxicology
- No studies have been conducted to evaluate the carcinogenic potential of verteporfin.
- Photodynamic therapy (PDT) as a class has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE), and mutations. In addition, other photodynamic therapeutic agents have been shown to increase the incidence of SCE in Chinese hamster ovary (CHO) cells irradiated with visible light and in Chinese hamster lung fibroblasts irradiated with near UV light, increase mutations and DNA-protein cross-linking in mouse L5178 cells, and increase DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. Verteporfin was not evaluated in these latter systems. It is not known how the potential for DNA damage with PDT agents translates into human risk.
- No effect on male or female fertility has been observed in rats following intravenous administration of verteporfin for injection up to 10 mg/kg/day (approximately 60- and 40-fold human exposure at 6 mg/m2 based on AUCinf in male and female rats, respectively).
# Clinical Studies
- Two adequate and well-controlled, double-masked, placebo-controlled, randomized studies were conducted in patients with classic-containing subfoveal CNV secondary to age-related macular degeneration. A total of 609 patients (Visudyne 402, placebo 207) were enrolled in these two studies. During these studies, retreatment was allowed every 3 months if fluorescein angiograms showed any recurrence or persistence of leakage. The placebo control (sham treatment) consisted of intravenous administration of Dextrose 5% in Water, followed by light application identical to that used for Visudyne therapy.
- The difference between treatment groups statistically favored Visudyne at the 1-year and 2-year analyses for visual acuity endpoints.
- The subgroup of patients with predominantly classic CNV lesions was more likely to exhibit a treatment benefit (N=242; Visudyne 159, placebo 83). Predominantly classic CNV lesions were defined as those in which the classic component comprised 50% or more of the area of the entire lesion. For the primary efficacy endpoint (percentage of patients who lost <3 lines of visual acuity), these patients showed a difference of approximately 28% between treatment groups at both Months 12 and 24 (67% for Visudyne patients compared to 40% for placebo patients, at Month 12; and 59% for Visudyne patients compared to 31% for placebo patients, at Month 24). Severe vision loss (≥6 lines of visual acuity from baseline) was experienced by 12% of Visudyne-treated patients compared to 34% of placebo-treated patients at Month 12, and by 15% of Visudyne-treated patients compared to 36% of placebo-treated patients at Month 24.
- Patients with predominantly classic CNV lesions that did not contain occult CNV exhibited the greatest benefit (N=134; Visudyne 90, placebo 44). At 1 year, these patients demonstrated a 49% difference between treatment groups when assessed by the <3 lines-lost definition (77% vs. 27%).
- Older patients (≥75 years), patients with dark irides, patients with occult lesions or patients with less than 50% classic CNV were less likely to benefit from Visudyne therapy.
- The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.
- Based on the TAP extension study, the average number of treatments per year were 3.5 in the first year after diagnosis, 2.4 in the second, 1.3 in the third, 0.4 in the fourth and 0.1 in the fifth year.
- One adequate and well-controlled, double-masked, placebo-controlled, randomized study was conducted in patients with subfoveal CNV secondary to pathologic myopia. A total of 120 patients (Visudyne 81, placebo 39) were enrolled in the study. The treatment dosing and retreatments were the same as in the AMD studies. The difference between treatment groups statistically favored Visudyne at the 1-year analysis but not at the 2-year analysis for visual acuity endpoints. For the primary efficacy endpoint (percentage of patients who lost <3 lines of visual acuity), patients at the 1-year timepoint showed a difference of approximately 19% between treatment groups (86% for Visudyne patients compared to 67% for placebo patients). However, by the 2-year timepoint, the effect was no longer statistically significant (79% for Visudyne patients compared to 72% for placebo patients).
- Based on the VIP-PM extension study in pathologic myopia, the average number of treatments per year were 3.5 in the first year after diagnosis, 1.8 in the second, 0.4 in the third, 0.2 in the fourth and 0.1 in the fifth.
- One open-label study was conducted in patients with subfoveal CNV secondary to presumed ocular histoplasmosis. A total of 26 patients were treated with Visudyne in the study. The treatment dosing and retreatments for Visudyne were the same as in the AMD studies. Visudyne-treated patients compare favorably with historical control data demonstrating a reduction in the number of episodes of severe visual acuity loss (>6 lines of loss).
- Based on the VOH extension study in presumed ocular histoplasmosis, the average number of treatments per year were 2.9 in the first year after diagnosis, 1.2 in the second, 0.2 in the third and 0.1 in the fourth.
# How Supplied
- Visudyne (verteporfin for injection) is supplied in a single use glass vial with a gray bromobutyl stopper and aluminum flip-off cap. It contains a lyophilized dark green cake with 15 mg verteporfin. The product is intended for intravenous injection only.
## Storage
There is limited information regarding Verteporfin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients who receive Visudyne will become temporarily photosensitive after the infusion. Patients should wear a wristband to remind them to avoid direct sunlight for 5 days. During that period, patients should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light. Sources of bright light include, but are not limited to, tanning salons, bright halogen lighting and high power lighting used in surgical operating rooms or dental offices. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 5 days following Visudyne administration.
- If treated patients must go outdoors in daylight during the first 5 days after treatment, they should protect all parts of their skin and their eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light.
- Patients should not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help inactivate the drug in the skin through a process called photobleaching.
- Following Visudyne treatment, patients may develop visual disturbances such as abnormal vision, vision decrease, or visual field defects that may interfere with their ability to drive or use machines. Patients should not drive or use machines as long as these symptoms persist.
# Precautions with Alcohol
- Alcohol-Verteporfin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VISUDYNE®
# Look-Alike Drug Names
There is limited information regarding Verteporfin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Verteporfin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Verteporfin is a photosensitizing agent that is FDA approved for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis. Common adverse reactions include injection site reaction, blurred vision, photopsia, reduced visual acuity, visual field defect.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Visudyne® (verteporfin for injection) therapy is indicated for the treatment of patients with predominantly classic subfoveal choroidal neovascularization due to age-related macular degeneration, pathologic myopia or presumed ocular histoplasmosis.
- There is insufficient evidence to indicate Visudyne for the treatment of predominantly occult subfoveal choroidal neovascularization.
- A course of Visudyne® (verteporfin for injection) therapy is a two-step process requiring administration of both drug and light.
- The first step is the intravenous infusion of Visudyne. The second step is the activation of Visudyne with light from a nonthermal diode laser.
- The physician should reevaluate the patient every 3 months and if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated.
- Lesion Size Determination
- The greatest linear dimension (GLD) of the lesion is estimated by fluorescein angiography and color fundus photography. All classic and occult CNV, blood and/or blocked fluorescence, and any serous detachments of the retinal pigment epithelium should be included for this measurement. Fundus cameras with magnification within the range of 2.4-2.6X are recommended. The GLD of the lesion on the fluorescein angiogram must be corrected for the magnification of the fundus camera to obtain the GLD of the lesion on the retina.
- Spot Size Determination
- The treatment spot size should be 1000 microns larger than the GLD of the lesion on the retina to allow a 500 micron border, ensuring full coverage of the lesion. The maximum spot size used in the clinical trials was 6400 microns.
- The nasal edge of the treatment spot must be positioned at least 200 microns from the temporal edge of the optic disc, even if this will result in lack of photoactivation of CNV within 200 microns of the optic nerve.
- Visudyne® Administration
- Reconstitute each vial of Visudyne with 7 mL of sterile Water for Injection to provide 7.5 mL containing 2 mg/mL. Reconstituted Visudyne must be protected from light and used within 4 hours. It is recommended that reconstituted Visudyne be inspected visually for particulate matter and discoloration prior to administration. Reconstituted Visudyne is an opaque dark green solution. Visudyne may precipitate in saline solutions. Do not use normal saline or other parenteral solutions, except 5% Dextrose for Injection, for dilution of the reconstituted Visudyne. Do not mix Visudyne in the same solution with other drugs.
- The volume of reconstituted Visudyne required to achieve the desired dose of 6 mg/m2 body surface area is withdrawn from the vial and diluted with 5% Dextrose for Injection to a total infusion volume of 30 mL. After dilution, protect from light and use within a maximum of 4 hours. The full infusion volume is administered intravenously over 10 minutes at a rate of 3 mL/minute, using an appropriate syringe pump and in-line filter. The clinical studies were conducted using a standard infusion line filter of 1.2 microns.
- Precautions should be taken to prevent extravasation at the injection site. If extravasation occurs, protect the site from light.
- Light Administration
- Initiate 689 nm wavelength laser light delivery to the patient 15 minutes after the start of the 10-minute infusion with Visudyne.
- Photoactivation of Visudyne is controlled by the total light dose delivered. In the treatment of choroidal neovascularization, the recommended light dose is 50 J/cm2 of neovascular lesion administered at an intensity of 600 mW/cm2. This dose is administered over 83 seconds.
- Light dose, light intensity, ophthalmic lens magnification factor and zoom lens setting are important parameters for the appropriate delivery of light to the predetermined treatment spot. Follow the laser system manuals for procedure set up and operation.
- The laser system must deliver a stable power output at a wavelength of 689±3 nm. Light is delivered to the retina as a single circular spot via a fiber optic and a slit lamp, using a suitable ophthalmic magnification lens.
- The following laser systems have been tested for compatibility with Visudyne and are approved for delivery of a stable power output at a wavelength of 689±3 nm:
- Coherent Opal Photoactivator laser console and modified Coherent LaserLink adapter, manufactured by Lumenis, Inc., 2400 Condensa Street, Santa Clara, CA 95051-0901,
- Zeiss VISULAS 690s laser and VISULINK® PDT adapter manufactured by Carl Zeiss Meditec Inc., 5160 Hacienda Drive, Dublin, CA 94568,
- Ceralas™ I laser system and Ceralink™ Slit Lamp Adapter manufactured by Biolitec Inc., 515 Shaker Road, East Longmeadow, MA 01028,
- Quantel Activis laser console and the ZSL30 ACT™, ZSL120 ACT™ and HSBMBQ ACT™ slit lamp adapters distributed by Quantel Medical, 601 Haggerty Lane, Bozeman, MT 59715.
- Concurrent Bilateral Treatment
- The controlled trials only allowed treatment of one eye per patient. In patients who present with eligible lesions in both eyes, physicians should evaluate the potential benefits and risks of treating both eyes concurrently. If the patient has already received previous Visudyne therapy in one eye with an acceptable safety profile, both eyes can be treated concurrently after a single administration of Visudyne. The more aggressive lesion should be treated first, at 15 minutes after the start of infusion. Immediately at the end of light application to the first eye, the laser settings should be adjusted to introduce the treatment parameters for the second eye, with the same light dose and intensity as for the first eye, starting no later than 20 minutes from the start of infusion.
- In patients who present for the first time with eligible lesions in both eyes without prior Visudyne therapy, it is prudent to treat only one eye (the most aggressive lesion) at the first course. One week after the first course, if no significant safety issues are identified, the second eye can be treated using the same treatment regimen after a second Visudyne infusion. Approximately 3 months later, both eyes can be evaluated and concurrent treatment following a new Visudyne infusion can be started if both lesions still show evidence of leakage.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Verteporfin in adult patients.
### Non–Guideline-Supported Use
- Intravenous verteporfin/laser therapy efficacious in nonmelanoma/metastatic carcinomas - 0.25 to 0.5 mg/kg (50 to 150 J/cm(2) laser light.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Verteporfin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Verteporfin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Verteporfin in pediatric patients.
# Contraindications
- Visudyne® (verteporfin for injection) is contraindicated for patients with porphyria or a known hypersensitivity to any component of this preparation.
# Warnings
- Following injection with Visudyne® (verteporfin for injection), care should be taken to avoid exposure of skin or eyes to direct sunlight or bright indoor light for 5 days. In the event of extravasation during infusion, the extravasation area must be thoroughly protected from direct light until the swelling and discoloration have faded in order to prevent the occurrence of a local burn which could be severe. If emergency surgery is necessary within 48 hours after treatment, as much of the internal tissue as possible should be protected from intense light.
- Patients who experience severe decrease of vision of ≥4 lines within 1 week after treatment should not be retreated, at least until their vision completely recovers to pretreatment levels and the potential benefits and risks of subsequent treatment are carefully considered by the treating physician.
- Use of incompatible lasers that do not provide the required characteristics of light for the photoactivation of Visudyne could result in incomplete treatment due to partial photoactivation of Visudyne , overtreatment due to overactivation of Visudyne , or damage to surrounding normal tissue.
### Precautions
- Standard precautions should be taken during infusion of Visudyne® (verteporfin for injection) to avoid extravasation. Examples of standard precautions include, but are not limited to:
- Free-flowing intravenous (IV) line should be established before starting Visudyne infusion and the line should be carefully monitored.
- Due to the possible fragility of vein walls of some elderly patients, it is strongly recommended that the largest arm vein possible, preferably antecutibal, be used for injection.
- Small veins in the back of the hand should be avoided.
- Extravasation of Visudyne, especially if the affected area is exposed to light, can cause severe pain, inflammation, swelling or discoloration at the injection site.
- If extravasation does occur, the infusion should be stopped immediately. The extravasation area must be thoroughly protected from direct light until swelling and discoloration have faded in order to prevent the occurrence of a local burn, which could be severe. Cold compresses should be applied to the injection site. Oral medications for pain relief may be administered.
- Visudyne therapy should be considered carefully in patients with moderate to severe hepatic impairment or biliary obstruction since there is no clinical experience with verteporfin in such patients.
- There is no clinical data related to the use of Visudyne in anesthetized patients. At a >10-fold higher dose given by bolus injection to sedated or anesthetized pigs, verteporfin caused severe hemodynamic effects, including death, probably as a result of complement activation. These effects were diminished or abolished by pretreatment with antihistamine and they were not seen in conscious nonsedated pigs. VISUDYNE resulted in a concentration-dependent increase in complement activation in human blood in vitro. At 10 µg/mL (approximately 5 times the expected plasma concentration in human patients), there was mild to moderate complement activation. At ≥100 µg/mL, there was significant complement activation. Signs (chest pain, syncope, dyspnea, and flushing) consistent with complement activation have been observed in <1% of patients administered Visudyne. Patients should be supervised during Visudyne infusion.
# Adverse Reactions
## Clinical Trials Experience
- Severe chest pain, vasovagal and hypersensitivity reactions have been reported. Vasovagal and hypersensitivity reactions on rare occasions can be severe. These reactions may include syncope, sweating, dizziness, rash, dyspnea, flushing and changes in blood pressure and heart rate. General symptoms can include headache, malaise, urticaria, and pruritus.
- The most frequently reported adverse events to Visudyne® (verteporfin for injection) are injection site reactions (including pain, edema, inflammation, extravasation, rashes, hemorrhage and discoloration) and visual disturbances (including blurred vision, flashes of light, decreased visual acuity and visual field defects, including scotoma). These events occurred in approximately 10%-30% of patients. The following events, listed by Body System, were reported more frequently with Visudyne therapy than with placebo therapy and occurred in 1%-10% of patients:
- Ocular Treatment Site: Blepharitis, cataracts, conjunctivitis/conjunctival injection, dry eyes, ocular itching, severe vision decrease with or without subretinal/retinal or vitreous hemorrhage
Asthenia, fever, flu syndrome, infusion related pain primarily presenting as back pain, photosensitivity reactions
Atrial fibrillation, hypertension, peripheral vascular disorder, varicose veins
Eczema
Constipation, gastrointestinal cancers, nausea
Anemia, white blood cell count decreased, white blood cell count increased
Elevated liver function tests
Albuminuria, creatinine increased
Arthralgia, arthrosis, myasthenia
Hypesthesia, sleep disorder, vertigo
Cough, pharyngitis, pneumonia
Cataracts, decreased hearing, diplopia, lacrimation disorder
Prostatic disorder
- Severe vision decrease, equivalent of ≥4 lines, within 7 days after treatment has been reported in 1%-5% of patients. Partial recovery of vision was observed in some patients. Photosensitivity reactions usually occurred in the form of skin sunburn following exposure to sunlight. The higher incidence of back pain in the Visudyne group occurred primarily during infusion.
## Postmarketing Experience
- The following adverse events have occurred either at low incidence (<1%) during clinical trials or have been reported during the use of Visudyne in clinical practice where these events were reported voluntarily from a population of unknown size and frequency of occurrence cannot be determined precisely. They have been chosen for inclusion based on factors such as seriousness, frequency of reporting, possible causal connection to Visudyne, or a combination of these factors:
- Ocular Treatment Site: Retinal detachment (nonrhegmatogenous), retinal or choroidal vessel nonperfusion, retinal pigment epithelial tear
- Non-ocular Events: Chest pain and other musculoskeletal pain during infusion
# Drug Interactions
- Drug interaction studies in humans have not been conducted with Visudyne.
- Verteporfin is rapidly eliminated by the liver, mainly as unchanged drug. Metabolism is limited and occurs by liver and plasma esterases. Microsomal cytochrome P450 does not appear to play a role in verteporfin metabolism.
- Based on the mechanism of action of verteporfin, many drugs used concomitantly could influence the effect of Visudyne therapy. Possible examples include the following:
- Calcium channel blockers, polymyxin B or radiation therapy could enhance the rate of Visudyne uptake by the vascular endothelium. Other photosensitizing agents (e.g., tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics and griseofulvin) could increase the potential for skin photosensitivity reactions. Compounds that quench active oxygen species or scavenge radicals, such as dimethyl sulfoxide, β-carotene, ethanol, formate and mannitol, would be expected to decrease Visudyne activity. Drugs that decrease clotting, vasoconstriction or platelet aggregation, e.g., thromboxane A2 inhibitors, could also decrease the efficacy of Visudyne therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Rat fetuses of dams administered verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis (approximately 40-fold human exposure at 6 mg/m2 based on AUCinf in female rats) exhibited an increase in the incidence of anophthalmia/microphthalmia. Rat fetuses of dams administered 25 mg/kg/day (approximately 125 fold the human exposure at 6 mg/m2 based on AUCinf in female rats) had an increased incidence of wavy ribs and anophthalmia/microphthalmia.
- In pregnant rabbits, a decrease in body weight gain and food consumption was observed in animals that received verteporfin for injection intravenously at ≥10 mg/kg/day during organogenesis. The no observed adverse effect level (NOAEL) for maternal toxicity was 3 mg/kg/day (approximately 7-fold human exposure at 6 mg/m2 based on body surface area). There were no teratogenic effects observed in rabbits at doses up to 10 mg/kg/day.
- There are no adequate and well-controlled studies in pregnant women. Visudyne should be used during pregnancy only if the benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Verteporfin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Verteporfin during labor and delivery.
### Nursing Mothers
- Verteporfin and its diacid metabolite have been found in the breast milk of one woman after a 6 mg/m2 infusion. The verteporfin breast milk levels were up to 66% of the corresponding plasma levels and declined below the limit of quantification (2 ng/mL) within 24 hours. The diacid metabolite had lower peak concentrations but persisted up to at least 48 hours.
- Because of the potential for serious adverse reactions in nursing infants from Visudyne, a decision should be made whether to discontinue nursing or postpone treatment, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Approximately 90% of the patients treated with Visudyne in the clinical efficacy trials were over the age of 65. A reduced treatment effect was seen with increasing age.
### Gender
There is no FDA guidance on the use of Verteporfin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Verteporfin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Verteporfin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Verteporfin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Verteporfin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Verteporfin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Verteporfin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Verteporfin in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- Overdose of drug and/or light in the treated eye may result in nonperfusion of normal retinal vessels with the possibility of severe decrease in vision that could be permanent. An overdose of drug will also result in the prolongation of the period during which the patient remains photosensitive to bright light. In such cases, it is recommended to extend the photosensitivity precautions for a time proportional to the overdose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Verteporfin in the drug label.
# Pharmacology
## Mechanism of Action
- Visudyne® (verteporfin for injection) therapy is a two-stage process requiring administration of both verteporfin for injection and nonthermal red light.
- Verteporfin is transported in the plasma primarily by lipoproteins. Once verteporfin is activated by light in the presence of oxygen, highly reactive, short-lived singlet oxygen and reactive oxygen radicals are generated. Light activation of verteporfin results in local damage to neovascular endothelium, resulting in vessel occlusion. Damaged endothelium is known to release procoagulant and vasoactive factors through the lipo-oxygenase (leukotriene) and cyclo-oxygenase (eicosanoids such as thromboxane) pathways, resulting in platelet aggregation, fibrin clot formation and vasoconstriction. Verteporfin appears to somewhat preferentially accumulate in neovasculature, including choroidal neovasculature. However, animal models indicate that the drug is also present in the retina. Therefore, there may be collateral damage to retinal structures following photoactivation including the retinal pigmented epithelium and outer nuclear layer of the retina. The temporary occlusion of choroidal neovascularization (CNV) following Visudyne therapy has been confirmed in humans by fluorescein angiography.
## Structure
- Visudyne® (verteporfin for injection) is a light activated drug used in photodynamic therapy. The finished drug product is a lyophilized dark green cake. Verteporfin is a 1:1 mixture of two regioisomers (I and II), represented by the following structures:
- The chemical names for the verteporfin regioisomers are:
- 9-methyl (I) and 13-methyl (II) trans-(±)-18-ethenyl-4,4a-dihydro-3,4-bis(methoxycarbonyl)-4a,8,14,19-tetramethyl-23H, 25H-benzo[b]porphine-9,13-dipropanoate
- The molecular formula is C41H42N4O8 with a molecular weight of approximately 718.8.
- Each mL of reconstituted VISUDYNE contains:
- ACTIVE: Verteporfin, 2 mg
- INACTIVES: ascorbyl palmitate, butylated hydroxytoluene, dimyristoyl phosphatidylcholine, egg phosphatidylglycerol and lactose
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Verteporfin in the drug label.
## Pharmacokinetics
- Following intravenous infusion, verteporfin exhibits a bi-exponential elimination with a terminal elimination half-life of approximately 5-6 hours. The extent of exposure and the maximal plasma concentration are proportional to the dose between 6 and 20 mg/m2. At the intended dose, pharmacokinetic parameters are not significantly affected by gender.
- Verteporfin is metabolized to a small extent to its diacid metabolite by liver and plasma esterases. NADPH-dependent liver enzyme systems (including the cytochrome P450 isozymes) do not appear to play a role in the metabolism of verteporfin. Elimination is by the fecal route, with less than 0.01% of the dose recovered in urine.
- In a study of patients with mild hepatic insufficiency (defined as having two abnormal hepatic function tests at enrollment), AUC and Cmax were not significantly different from the control group; half-life, however, was significantly increased by approximately 20%.
## Nonclinical Toxicology
- No studies have been conducted to evaluate the carcinogenic potential of verteporfin.
- Photodynamic therapy (PDT) as a class has been reported to result in DNA damage including DNA strand breaks, alkali-labile sites, DNA degradation, and DNA-protein cross links which may result in chromosomal aberrations, sister chromatid exchanges (SCE), and mutations. In addition, other photodynamic therapeutic agents have been shown to increase the incidence of SCE in Chinese hamster ovary (CHO) cells irradiated with visible light and in Chinese hamster lung fibroblasts irradiated with near UV light, increase mutations and DNA-protein cross-linking in mouse L5178 cells, and increase DNA-strand breaks in malignant human cervical carcinoma cells, but not in normal cells. Verteporfin was not evaluated in these latter systems. It is not known how the potential for DNA damage with PDT agents translates into human risk.
- No effect on male or female fertility has been observed in rats following intravenous administration of verteporfin for injection up to 10 mg/kg/day (approximately 60- and 40-fold human exposure at 6 mg/m2 based on AUCinf in male and female rats, respectively).
# Clinical Studies
- Two adequate and well-controlled, double-masked, placebo-controlled, randomized studies were conducted in patients with classic-containing subfoveal CNV secondary to age-related macular degeneration. A total of 609 patients (Visudyne 402, placebo 207) were enrolled in these two studies. During these studies, retreatment was allowed every 3 months if fluorescein angiograms showed any recurrence or persistence of leakage. The placebo control (sham treatment) consisted of intravenous administration of Dextrose 5% in Water, followed by light application identical to that used for Visudyne therapy.
- The difference between treatment groups statistically favored Visudyne at the 1-year and 2-year analyses for visual acuity endpoints.
- The subgroup of patients with predominantly classic CNV lesions was more likely to exhibit a treatment benefit (N=242; Visudyne 159, placebo 83). Predominantly classic CNV lesions were defined as those in which the classic component comprised 50% or more of the area of the entire lesion. For the primary efficacy endpoint (percentage of patients who lost <3 lines of visual acuity), these patients showed a difference of approximately 28% between treatment groups at both Months 12 and 24 (67% for Visudyne patients compared to 40% for placebo patients, at Month 12; and 59% for Visudyne patients compared to 31% for placebo patients, at Month 24). Severe vision loss (≥6 lines of visual acuity from baseline) was experienced by 12% of Visudyne-treated patients compared to 34% of placebo-treated patients at Month 12, and by 15% of Visudyne-treated patients compared to 36% of placebo-treated patients at Month 24.
- Patients with predominantly classic CNV lesions that did not contain occult CNV exhibited the greatest benefit (N=134; Visudyne 90, placebo 44). At 1 year, these patients demonstrated a 49% difference between treatment groups when assessed by the <3 lines-lost definition (77% vs. 27%).
- Older patients (≥75 years), patients with dark irides, patients with occult lesions or patients with less than 50% classic CNV were less likely to benefit from Visudyne therapy.
- The safety and efficacy of Visudyne beyond 2 years have not been demonstrated.
- Based on the TAP extension study, the average number of treatments per year were 3.5 in the first year after diagnosis, 2.4 in the second, 1.3 in the third, 0.4 in the fourth and 0.1 in the fifth year.
- One adequate and well-controlled, double-masked, placebo-controlled, randomized study was conducted in patients with subfoveal CNV secondary to pathologic myopia. A total of 120 patients (Visudyne 81, placebo 39) were enrolled in the study. The treatment dosing and retreatments were the same as in the AMD studies. The difference between treatment groups statistically favored Visudyne at the 1-year analysis but not at the 2-year analysis for visual acuity endpoints. For the primary efficacy endpoint (percentage of patients who lost <3 lines of visual acuity), patients at the 1-year timepoint showed a difference of approximately 19% between treatment groups (86% for Visudyne patients compared to 67% for placebo patients). However, by the 2-year timepoint, the effect was no longer statistically significant (79% for Visudyne patients compared to 72% for placebo patients).
- Based on the VIP-PM extension study in pathologic myopia, the average number of treatments per year were 3.5 in the first year after diagnosis, 1.8 in the second, 0.4 in the third, 0.2 in the fourth and 0.1 in the fifth.
- One open-label study was conducted in patients with subfoveal CNV secondary to presumed ocular histoplasmosis. A total of 26 patients were treated with Visudyne in the study. The treatment dosing and retreatments for Visudyne were the same as in the AMD studies. Visudyne-treated patients compare favorably with historical control data demonstrating a reduction in the number of episodes of severe visual acuity loss (>6 lines of loss).
- Based on the VOH extension study in presumed ocular histoplasmosis, the average number of treatments per year were 2.9 in the first year after diagnosis, 1.2 in the second, 0.2 in the third and 0.1 in the fourth.
# How Supplied
- Visudyne (verteporfin for injection) is supplied in a single use glass vial with a gray bromobutyl stopper and aluminum flip-off cap. It contains a lyophilized dark green cake with 15 mg verteporfin. The product is intended for intravenous injection only.
## Storage
There is limited information regarding Verteporfin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients who receive Visudyne will become temporarily photosensitive after the infusion. Patients should wear a wristband to remind them to avoid direct sunlight for 5 days. During that period, patients should avoid exposure of unprotected skin, eyes or other body organs to direct sunlight or bright indoor light. Sources of bright light include, but are not limited to, tanning salons, bright halogen lighting and high power lighting used in surgical operating rooms or dental offices. Prolonged exposure to light from light-emitting medical devices such as pulse oximeters should also be avoided for 5 days following Visudyne administration.
- If treated patients must go outdoors in daylight during the first 5 days after treatment, they should protect all parts of their skin and their eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light.
- Patients should not stay in the dark and should be encouraged to expose their skin to ambient indoor light, as it will help inactivate the drug in the skin through a process called photobleaching.
- Following Visudyne treatment, patients may develop visual disturbances such as abnormal vision, vision decrease, or visual field defects that may interfere with their ability to drive or use machines. Patients should not drive or use machines as long as these symptoms persist.
# Precautions with Alcohol
- Alcohol-Verteporfin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VISUDYNE®[2]
# Look-Alike Drug Names
There is limited information regarding Verteporfin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Verteporfin | |
2055776dbcc22699a3269a683c532a180e773846 | wikidoc | Victor Ling | Victor Ling
# Overview
Dr. Victor Ling is an award-winning Canadian researcher in the field of medicine. Ling's research focuses on drug resistance in cancer. He is best known for his discovery of P-glycoprotein, one of the proteins responsible for multidrug resistance.
Ling was born in China, and emigrated to Canada as a child. He received his bachelor's degree in 1966 from the University of Toronto and his PhD in 1969 from the University of British Columbia. In 2006, he was awarded an honorary doctorate from Trinity Western University. He undertook post-doctoral training with nobel-laureate Dr. Fred Sanger at Cambridge University. Ling is currently Assistant Dean of the Faculty of Medicine at the University of British Columbia and Vice-President, Discovery at the BC Cancer Agency in Vancouver, British Columbia.
# Honours
- 1990, awarded the Gairdner Award from the Gairdner Foundation for outstanding contributions to medical science
- 1991, awarded the Charles F. Kettering Prize
- 1991, awarded the Steiner Award, the highest honour in cancer research
- 1994, awarded the Robert L. Noble Prize by the National Cancer Institute of Canada
- 2000, appointed to the Order of British Columbia | Victor Ling
# Overview
Dr. Victor Ling is an award-winning Canadian researcher in the field of medicine. Ling's research focuses on drug resistance in cancer. He is best known for his discovery of P-glycoprotein, one of the proteins responsible for multidrug resistance.
Ling was born in China, and emigrated to Canada as a child. He received his bachelor's degree in 1966 from the University of Toronto and his PhD in 1969 from the University of British Columbia. In 2006, he was awarded an honorary doctorate from Trinity Western University. He undertook post-doctoral training with nobel-laureate Dr. Fred Sanger at Cambridge University. Ling is currently Assistant Dean of the Faculty of Medicine at the University of British Columbia and Vice-President, Discovery at the BC Cancer Agency in Vancouver, British Columbia.
# Honours
- 1990, awarded the Gairdner Award from the Gairdner Foundation for outstanding contributions to medical science
- 1991, awarded the Charles F. Kettering Prize
- 1991, awarded the Steiner Award, the highest honour in cancer research
- 1994, awarded the Robert L. Noble Prize by the National Cancer Institute of Canada
- 2000, appointed to the Order of British Columbia
# External links
- Webpage at the BC Cancer Research Centre
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Victor_Ling | |
901a3523952fe8eb7f6ffb830b97c98016e787e9 | wikidoc | Vin Mariani | Vin Mariani
Vin Mariani (French: Mariani's wine) was a tonic created circa 1863 by Angelo Mariani, a chemist who became intrigued with coca and its economic potential after reading Paolo Mantegazza’s paper on coca's effects. In 1863 Mariani started marketing a wine called Vin Mariani which was made from Bordeaux wine treated with coca leaves. The ethanol in the wine acted as a solvent and extracted the cocaine from the coca leaves, altering the drink’s effect. It originally contained 6 mg of cocaine per fluid ounce of wine, but Vin Mariani which was to be exported contained 7.2 mg per ounce in order to compete with the higher cocaine content of similar drinks in the United States.
This tonic was copied by John S. Pemberton in 1884, originally as a cocawine called Pemberton's French Wine Coca. In 1885, when Atlanta and Fulton County passed Prohibition legislation, Pemberton responded by developing Coca-Cola, essentially a carbonated, non-alcoholic version of Mariani's wine with the addition of cola. The beverage was named Coca-Cola because originally, the stimulant mixed in the beverage was coca leaves from South America. In addition, the drink was flavored using kola nuts, the beverage's source of caffeine. Therefore, Angelo Mariani is sometimes thought of as the "grandfather of Coca-Cola."
When cocaine is administered on its own it yields two key active compounds, benzoylecgonine and ecgonine methyl ester. When combined with alcohol, as in Vin Mariani, the mixture forms a powerful psychoactive: cocaethylene (which is both more euphorigenic and has higher cardiovascular toxicity than cocaine by itself).
Vin Mariani was very popular in its day, even among royalty such as Queen Victoria of Great Britain and Ireland. Pope Leo XIII and later Pope Saint Pius X were both Vin Mariani drinkers. Pope Leo awarded a Vatican gold medal to the wine, and also appeared on a poster endorsing it.
A group of UK investors, Mariani Amalgamated Ltd, has recently revived the wine.
Reference: VinCocaMariani.com
cs:Vin Mariani
de:Vin Mariani
nl:Vin Mariani
sv:Vin Mariani | Vin Mariani
Vin Mariani (French: Mariani's wine) was a tonic created circa 1863 by Angelo Mariani, a chemist who became intrigued with coca and its economic potential after reading Paolo Mantegazza’s paper on coca's effects. In 1863 Mariani started marketing a wine called Vin Mariani which was made from Bordeaux wine treated with coca leaves. The ethanol in the wine acted as a solvent and extracted the cocaine from the coca leaves, altering the drink’s effect. It originally contained 6 mg of cocaine per fluid ounce of wine, but Vin Mariani which was to be exported contained 7.2 mg per ounce in order to compete with the higher cocaine content of similar drinks in the United States.
This tonic was copied by John S. Pemberton in 1884, originally as a cocawine called Pemberton's French Wine Coca. In 1885, when Atlanta and Fulton County passed Prohibition legislation, Pemberton responded by developing Coca-Cola, essentially a carbonated, non-alcoholic version of Mariani's wine with the addition of cola. The beverage was named Coca-Cola because originally, the stimulant mixed in the beverage was coca leaves from South America. In addition, the drink was flavored using kola nuts, the beverage's source of caffeine. Therefore, Angelo Mariani is sometimes thought of as the "grandfather of Coca-Cola."
When cocaine is administered on its own it yields two key active compounds, benzoylecgonine and ecgonine methyl ester. When combined with alcohol, as in Vin Mariani, the mixture forms a powerful psychoactive: cocaethylene (which is both more euphorigenic and has higher cardiovascular toxicity than cocaine by itself).
Vin Mariani was very popular in its day, even among royalty such as Queen Victoria of Great Britain and Ireland. Pope Leo XIII and later Pope Saint Pius X were both Vin Mariani drinkers. Pope Leo awarded a Vatican gold medal to the wine, and also appeared on a poster endorsing it.
A group of UK investors, Mariani Amalgamated Ltd, has recently revived the wine.
Reference: VinCocaMariani.com
cs:Vin Mariani
de:Vin Mariani
nl:Vin Mariani
sv:Vin Mariani
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Vin_Mariani | |
6943491eb9b041d07a57b68e016556a1c4509322 | wikidoc | Vinblastine | Vinblastine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Vinblastine is an antineoplastic agent that is FDA approved for the treatment of palliative treatment of Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye staging system),Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated),Histiocytic lymphoma,Mycosis fungoides (advanced stages),Advanced carcinoma of the testis,Kaposi's sarcoma,
Letterer-Siwe disease (histiocytosis X). There is a Black Box Warning for this drug as shown here. Common adverse reactions include leukopenia,alopecia,constipation, anorexia, nausea, vomiting, abdominal pain, ileus, vesiculation of the mouth, pharyngitis, diarrhea,Hypertension, Malaise, bone pain, weakness, pain in tumor-containing tissue, dizziness, jaw pain, skin vesiculation,.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Vinblastine Sulfate Injection is indicated in the palliative treatment of the following:
- Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye staging system)
- Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated)
- Histiocytic lymphoma
- Mycosis fungoides (advanced stages)
- Advanced carcinoma of the testis
- Kaposi's sarcoma
- Letterer-Siwe disease (histiocytosis X)
- Choriocarcinoma resistant to other chemotherapeutic agents
- Carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy
Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose-limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine sulfate is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. Such combination therapy produces a greater percentage of response than does a single-agent regimen. These principles have been applied, for example, in the chemotherapy of Hodgkin’s disease.
- Vinblastine sulfate has been shown to be one of the most effective single agents for the treatment of Hodgkin’s disease. Advanced Hodgkin’s disease has also been successfully treated with several multiple-drug regimens that included vinblastine sulfate. Patients who had relapses after treatment with the MOPP program— mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, prednisone and procarbazine—have likewise responded to combination-drug therapy that included vinblastine sulfate. A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate instead of vincristine sulfate is an alternative therapy for previously untreated patients with advanced Hodgkin’s disease.
- Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma and choriocarcinoma) are sensitive to vinblastine sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine sulfate is administered six to eight hours prior to the administration of bleomycin; this schedule permits more cells to be arrested during metaphase, the stage of the cell cycle in which bleomycin is active.
- This preparation is for intravenous use only.
- WHEN DISPENSING VINBLASTINE SULFATE INJECTION IN OTHER THAN THE ORIGINAL CONTAINER, IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICH BEARS THE FOLLOWING STATEMENT: “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” . A syringe containing a specific dose must be labeled, using the auxiliary sticker provided to state: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.”
- Caution–It is extremely important that the intravenous needle or catheter be properly positioned before any vinblastine sultate is injected. Leakage into surrounding tissue during intravenous administration of vinblastine sulfate may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.
- There are variations in the depth of the leukopenic response that follows therapy with vinblastine sulfate. For this reason, it is
recommended that the drug be given no more frequently than once every seven days.
- It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m2 of body surface area (bsa). Thereafter, white blood cell counts should be made to determine the patient’s sensitivity to vinblastine sulfate.
- A simplified and conservative incremental approach to dosage at weekly intervals for adults may be outlined as follows:
- First dose ....................................... 3.7 mg/m2 bsa
- Second dose .................................. 5.5 mg/m2 bsa
- Third dose ...................................... 7.4 mg/m2 bsa
- Fourth dose .................................. 9.25 mg/m2 bsa
- Fifth dose ..................................... 11.1 mg/m2 bsa
- The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m2 bsa for adults is reached. The dose should not be increased after that dose which reduces the white cell count to approximately 3,000 cells/mm3. In some adults, 3.7 mg/m2 bsa may produce this leukopenia; other adults may require more than 11.1 mg/m2 bsa; and, very rarely, as much as 18.5 mg/m2 bsa may be necessary. For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m2 bsa.
- When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of one increment smaller than this should be administered at weekly intervals for maintenance. Thus, the patient is receiving the maximum dose that does not cause leukopenia. It should be emphasized that, even though seven days have elapsed, the next dose of vinblastine sulfate should not be given until the white cell count has returned to at least 4,000/mm3. In some cases, oncolytic activity may be encountered before leukopenic effect. When this occurs, there is no need to increase the size of subsequent doses.
## Off-Label Use and Dosage (Adult)
### Non–Guideline-Supported Use
- Carcinoma of bladder: MVAC regimen, vinBLAStine 3 mg/m(2) IV on days 2, 15, and 22; in combination with methotrexate 30 mg/m(2) on days 1, 15, and 22; doxorubicin 30 mg/m(2) on day 2; cisplatin 70 mg/m(2) IV on day 2; repeat every 28 days
Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, et al. (2001). "Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924". J. Clin. Oncol. 19 (10): 2638–46. PMID 11352955..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Carcinoma of prostate: optimal dose and timing has not been defined in this setting; clinical trials have used doses of vinBLAStine of 4 mg/m(2) per wk IV for 6 wk, and then 2 wk off: optimal dose and timing has not been defined in this setting; clinical trials have used doses of vinBLAStine of 4 mg/m(2) per wk IV for 6 wk, and then 2 wk off Hudes G, Einhorn L, Ross E, Balsham A, Loehrer P, Ramsey H, et al. (1999). "Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial". J. Clin. Oncol. 17 (10): 3160–6. PMID 10506613.
- Germ cell tumor of ovary: optimal dose and timing of vinBLAStine has not been defined in this setting; PVB regimen has been used in clinical trials and consists of cisplatin 20 mg/m(2) IV) daily for 5 days, vinBLAStine 12 mg/m(2) IV push on day 1, and bleomycin 20 units/m(2) (maximum dose 30 units) IV push once weekly; administer every 3 weeks for 3 to 4 courses Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ (1987). "Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide". N. Engl. J. Med. 316 (23): 1435–40. doi:10.1056/NEJM198706043162302. PMID 2437455.
- VinBLAStine 0.1 milligram/kilogram was dissolved in 500 to 1000 milliliters of normal saline and infused intravenously over 6 to 8 hours.Ahn YS, Harrington WJ, Mylvaganam R, Allen LM, Pall LM (1984). "Slow infusion of vinca alkaloids in the treatment of idiopathic thrombocytopenic purpura". Ann. Intern. Med. 100 (2): 192–6. PMID 6537881.
- Metastatic malignant melanoma: optimal dose and timing have not been defined in this setting; CVD+IL-2I regimen has been used in a clinical trial and consists of cisplatin 20 mg/m(2) IV days 1 to 4, vinBLAStine 1.6 mg/m(2) IV days 1 to 5, dacarbazine 800 mg/m(2) IV day 1, IL-2 nine million units/m(2) continuous infusion days 1 to 4, interferon alfa 5 million units/m(2) subQ days 1 to 5, 7, 9, 11, and 13; repeat cycle every 21 days Legha SS, Ring S, Bedikian A, Plager C, Eton O, Buzaid AC, et al. (1996). "Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha". Ann. Oncol. 7 (8): 827–35. PMID 8922197.
- Non-small cell lung cancer: Adjuvant treatment, 4 mg/m(2) IV, in combination with various doses of cisplatin; administer once weekly until day 29 and then once every 2 wk after day 43 until the last dose of cisplatin Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J (2004). "Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer". N. Engl. J. Med. 350 (4): 351–60. doi:10.1056/NEJMoa031644. PMID 14736927.
- Renal cell carcinoma: 0.1 mg/kg IV every 3 weeks; in combination with interferon alfa-2a, 3 million units IM/subQ 3 times a week for 1 week then 18 million units 3 times a week thereafter has been used Pyrhönen S, Salminen E, Ruutu M, Lehtonen T, Nurmi M, Tammela T, et al. (1999). "Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer". J. Clin. Oncol. 17 (9): 2859–67. PMID 10561363.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Vinblastine Sulfate Injection is indicated in the palliative treatment of the following:
- Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye staging system)
- Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated)
- Histiocytic lymphoma
- Mycosis fungoides (advanced stages)
- Advanced carcinoma of the testis
- Kaposi's sarcoma
- Letterer-Siwe disease (histiocytosis X)
- Choriocarcinoma resistant to other chemotherapeutic agents
- Carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy
Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose-limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine sulfate is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. Such combination therapy produces a greater percentage of response than does a single-agent regimen. These principles have been applied, for example, in the chemotherapy of Hodgkin’s disease.
- Vinblastine sulfate has been shown to be one of the most effective single agents for the treatment of Hodgkin’s disease. Advanced Hodgkin’s disease has also been successfully treated with several multiple-drug regimens that included vinblastine sulfate. Patients who had relapses after treatment with the MOPP program— mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, prednisone and procarbazine—have likewise responded to combination-drug therapy that included vinblastine sulfate. A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate instead of vincristine sulfate is an alternative therapy for previously untreated patients with advanced Hodgkin’s disease.
- Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma and choriocarcinoma) are sensitive to vinblastine sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine sulfate is administered six to eight hours prior to the administration of bleomycin; this schedule permits more cells to be arrested during metaphase, the stage of the cell cycle in which bleomycin is active.
- A review of published literature from 1993 to 1995 showed that initial doses of vinblastine sulfate in pediatric patients varied depending on the schedule used and whether vinblastine sulfate was administered as a single agent or incorporated within a particular chemotherapeutic regimen. As a single agent for Letterer-Siwe disease (histiocytosis X), the initial dose of vinblastine sulfate was reported as 6.5 mg/m2. When vinblastine sulfate was used in combination with other chemotherapeutic agents for the treatment of Hodgkin’s disease, the initial dose was reported as 6 mg/m2. For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m2 in a combination regimen. Dose modifications should be guided by hematologic tolerance.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
- Vinblastine sulfate is contraindicated in patients who have significant granulocytopenia unless this is a result of the disease being treated. It should not be used in the presence of bacterial infections. Such infections must be brought under control prior to the initiation of therapy with vinblastine sulfate.
# Warnings
- This preparation is for intravenous use only. It should be administered by individuals experienced in the administration of vinblastine sulfate. The intrathecal administration of vinblastine sulfate usually results in death. Syringes containing this product should be labeled, using the auxiliary sticker provided, to state ‘‘FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES. ’’
- Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled ‘‘DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.’’
- After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.
- There are no published cases of survival following intrathecal administration of vinblastine sulfate to base treatment on. However, based on the published management of survival cases involving the related vinca alkaloid vincristine sulfate1-3, if vinblastine sulfate is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:
- Removal of as much CSF as is safely possible through the lumbar access.
- Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer’s solution. Fresh frozen plasma should be requested and, when available, 25 mL should be added to every 1 liter of lactated Ringer’s solution.
- Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer’s solution should be given by continuous infusion at 150 mL/hour, or at a rate of 75 mL/hour when fresh frozen plasma has been added as above.
- The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dL.
- The following measures have also been used in addition but may not be essential:
- Glutamic acid, 10 grams, has been given intravenously over 24 hours, followed by 500 mg three times daily by mouth for 1 month.
- Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/hour for 24 hours, then bolus doses of 25 mg every 6 hours for 1 week. Pyridoxine has been given at a dose of 50 mg every 8 hours by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.
### Precautions
- Toxicity may be enhanced in the presence of hepatic insufficiency.
- If leukopenia with less than 2,000 white blood cells/mm3 occurs following a dose of vinblastine sulfate, the patient should be watched carefully for evidence of infection until the white blood cell count has returned to a safe level.
- When cachexia or ulcerated areas of the skin surface are present, there may be a more profound leukopenic response to the drug; therefore, its use should be avoided in older persons suffering from either of these conditions.
- In patients with malignant-cell infiltration of the bone marrow, the leukocyte and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine sulfate. Further use of the drug in such patients is inadvisable.
- Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C and may require aggressive treatment, particularly when there is pre-existing pulmonary dysfunction. The onset may be within minutes or several hours after the vinca is injected and may occur up to two weeks following a dose of mitomycin. Progressive dyspnea requiring chronic therapy may occur. Vinblastine should not be readministered.
- Care should be recommended in patients with ischemic cardiac disease.
- The use of small amounts of vinblastine sulfate daily for long periods is not advised, even though the resulting total weekly dosage may be similar to that recommended. Little or no added therapeutic effect has been demonstrated when such regimens have been used. Strict adherence to the recommended dosage schedule is very important. When amounts equal to several times the recommended weekly dosage were given in seven daily installments for long periods, convulsions, severe and permanent central nervous system damage, and even death occurred.
- Care must be taken to avoid contamination of the eye with concentrations of vinblastine sulfate used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed with water immediately and thoroughly.
# Adverse Reactions
## Clinical Trials Experience
- Prior to the use of the drug, patients should be advised of the possibility of untoward symptoms.
- In general, the incidence of adverse reactions attending the use of vinblastine sulfate appears to be related to the size of the dose employed. With the exception of epilation, leukopenia and neurologic side effects, adverse reactions generally have not persisted for longer than 24 hours. Neurologic side effects are not common; but when they do occur, they often last for more than 24 hours. Leukopenia, the most common adverse reaction, is usually the dose-limiting factor.
- The following are manifestations that have been reported as adverse reactions, in decreasing order of frequency. The most common adverse reactions are underlined:
- Leukopenia (granulocytopenia), anemia, thrombocytopenia (myelosuppression).
- Alopecia is common. A single case of light sensitivity associated with this product has been reported.
- Constipation, anorexia, nausea, vomiting, abdominal pain, ileus, vesiculation of the mouth, pharyngitis, diarrhea, hemorrhagic enterocolitis, bleeding from an old peptic ulcer and rectal bleeding.
- Numbness of digits (paresthesias), loss of deep tendon reflexes, peripheral neuritis, mental depression, headache, convulsions.
- Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve.
- Manifestations include partial or total deafness which may be temporary or permanent, and difficulties with balance including dizziness, nystagmus and vertigo. Particular caution is warranted when vinblastine sulfate is used in combination with other agents known to be ototoxic such as the platinum-containing oncolytics.
- Hypertension—Cardiac effects such as myocardial infarction, angina pectoris and transient abnormalities of ECG related to coronary ischemia have been reported very rarely. Cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin and cisplatin. Raynaud’s phenomenon has also been reported with this combination.
- Malaise, bone pain, weakness, pain in tumor-containing tissue, dizziness, jaw pain, skin vesiculation, hypertension, Raynaud’s phenomenon when patients are being treated with vinblastine sulfate in combination with bleomycin and cis-platinum for testicular cancer. The syndrome of inappropriate secretion of antidiuretic hormone has occurred with higher than recommended doses.
- Nausea and vomiting usually may be controlled with ease by antiemetic agents. When epilation develops, it frequently is not total; and, in some cases, hair regrows while maintenance therapy continues.
- Extravasation during intravenous injection may lead to cellulitis and phlebitis. If the amount of extravasation is great, sloughing may occur.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of vinblastine in the drug label.
# Drug Interactions
- The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vinblastine sulfate to this interaction is not certain. The interaction may result from either reduced absorption of phenytoin or an increase in the rate of its metabolism and elimination.
- Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects. Enhanced toxicity has been reported in patients receiving concomitant erythromycin
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Caution is necessary with the administration of all oncolytic drugs during pregnancy. Information on the use of vinblastine sulfate during human pregnancy is very limited. Animal studies with vinblastine sulfate suggest that teratogenic effects may occur. Vinblastine sulfate can cause fetal harm when administered to a pregnant woman. Laboratory animals given this drug early in pregnancy suffer resorption of the conceptus; surviving fetuses demonstrate gross deformities. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
- Aspermia has been reported in man. Animal studies show metaphase arrest and degenerative changes in germ cells.
- Leukopenia (granulocytopenia) may reach dangerously low levels following administration of the higher recommended doses. It is therefore important to follow the dosage technique. Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of vinblastine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of vinblastine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vinblastine sulfate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of vinblastine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of vinblastine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of vinblastine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of vinblastine with respect to specific racial populations.
### Renal Impairment
- A reduction of 50% in the dose of vinblastine sulfate is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL. Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.
- The duration of maintenance therapy varies according to the disease being treated and the combination of antineoplastic agents being used. There are differences of opinion regarding the duration of maintenance therapy with the same protocol for a particular disease; for example, various durations have been used with the MOPP program in treating Hodgkin’s disease. Prolonged chemotherapy for maintaining remissions involves several risks, among which are life-threatening infectious diseases, sterility and possibly the appearance of other cancers through suppression of immune surveillance.
- In some disorders, survival following complete remission may not be as prolonged as that achieved with shorter periods of maintenance therapy. On the other hand, failure to provide maintenance therapy in some patients may lead to unnecessary relapse; complete remissions in patients with testicular cancer, unless maintained for at least two years, often result in early relapse.
- The dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous infusion or directly into a vein. The latter procedure is readily adaptable to outpatient therapy. In either case, the injection may be completed in about one minute. If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine sulfate is spilled extra-vascularly, cellulitis and/or phlebitis will not occur. To minimize further the possibility of extra vascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal of the needle. The dose should not be diluted in large volumes of diluent (i.e., 100 to 250 mL) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), since this frequently results in irritation of the vein and increases the chance of extravasation.
- Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis or varicosity.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Procedures for proper handling and disposal of anti-cancer drugs should be considered. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate
### Hepatic Impairment
There is no FDA guidance on the use of vinblastine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of vinblastine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of vinblastine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of vinblastine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of vinblastine in the drug label.
# Overdosage
- Side effects following the use of vinblastine sulfate are dose related. Therefore, following administration of more than the recommended dose, patients can be expected to experience these effects in an exaggerated fashion.There is no specific antidote. In addition, neurotoxicity similar to that with vincristine sulfate may be observed. Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic insufficiency.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. . *In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient. Overdoses of vinblastine sulfate have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.
- Supportive care should include the following: (1) prevention of side effects that result from the syndrome of inappropriate secretion of antidiuretic hormone (this would include restriction of the volume of daily fluid intake to that of the urine output plus insensible loss and perhaps the administration of a diuretic affecting the function of the loop of Henle and the distal tubule); (2) administration of an anticonvulsant; (3) prevention of ileus: (4) monitoring the cardiovascular system; and (5) determining daily blood counts for guidance in transfusion requirements and assessing the risk of infection. The major effect of excessive doses of vinblastine sulfate will be myelosuppression, which may be life-threatening. There is no information regarding the effectiveness of dialysis nor of cholestyramine for the treatment of overdosage.
- Vinblastine sulfate in the dry state is irregularly and unpredictably absorbed from the gastrointestinal tract following oral administration. Absorption of the solution has not been studied. If vinblastine is swallowed, activated charcoal in a water slurry may be given by mouth along with a cathartic. The use of cholestyramine in this situation has not been reported.
- Symptoms of overdose will appear when greater-than-recommended doses are given. Any dose of vinblastine sulfate that results in elimination of platelets and neutrophils from blood and marrow and their precursors from marrow should be considered life-threatening. The exact dose that will do this in all patients is unknown. Overdoses occurring during prolonged consecutive-day infusions may be more toxic than the same total dose given by rapid intravenous injection. The intravenous median lethal dose in mice is 10 mg/kg body weight; in rats, it is 2.9 mg/kg. The oral median lethal dose in rats is 7 mg/kg.
- Protect the patient’s airway and support ventilation and perfusion.
- Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc.
- Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying if the drug has been swallowed.
- Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
# Pharmacology
## Mechanism of Action
- Experimental data indicate that the action of vinblastine sulfate is different from that of other recognized antineoplastic agents. Tissue-culture studies suggest an interference with metabolic pathways of amino acids leading from glutamic acid to the citric acid cycle and to urea. In vivo experiments tend to confirm the in vitro results. A number of studies in vitro and in vivo have demonstrated that vinblastine sulfate produces a stathmokinetic effect and various atypical mitotic figures. The therapeutic responses, however, are not fully explained by the cytologic changes, since these changes are sometimes observed clinically and experimentally in the absence of any oncolytic effects.
- Reversal of the antitumor effect of vinblastine sulfate by glutamic acid or tryptophan has been observed. In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinblastine sulfate. Aspartic acid was relatively ineffective in reversing the antitumor effect.
- Other studies indicate that vinblastine sulfate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis. The mechanism of action of vinblastine has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
## Structure
- Vinblastine sulfate is the salt of an alkaloid extracted from Vinca rosea Linn., a common flowering herb known as the periwinkle (more properly known as Catharanthus roseus G. Don). Previously, the generic name was vincaleukoblastine, abbreviated VLB. It is a stathmokinetic oncolytic agent. When treated in vitro with this preparation, growing cells are arrested in metaphase.
- Chemical and physical evidence indicate that vinblastine sulfate is a dimeric alkaloid containing both indole and dihydroindole moieties.
- The accompanying structural formula has been proposed.
- Each mL contains: Vinblastine sulfate 1 mg; sodium chloride 9 mg; benzyl alcohol 0.9% (v/v) as a preservative; Water for Injection q.s. (pH 3.5 to 5.0).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of vinblastine in the drug label.
## Pharmacokinetics
- Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle and terminal half-lives are 3.7 minutes, 1.6 hours and 24.8 hours, respectively. The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs. Low body stores are present at 48 and 72 hours after injection.Since the major route of excretion may be through the biliary system, toxicity from this drug may be in creased when there is hepatic excretory insufficiency.The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes such as erythromycin. Enhanced toxicity has been reported in patients receiving concomitant erythromycin . Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the feces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over nine days, 30 to 36% of radioactivity was found in the bile and 12 to 17% in the urine. A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen and kidney two hours after injection.
- Hematologic Effects
- Clinically, leukopenia is an expected effect of vinblastine sulfate, and the level of the leukocyte count is an important guide to therapy with this drug. In general, the larger the dose employed, the more profound and longer lasting the leukopenia will be. The fact that the white blood cell count returns to normal levels after drug-induced leukopenia is an indication that the white cell-producing mechanism is not permanently depressed. Usually, the white count has completely returned to normal after the virtual disappearance of white cells from the peripheral blood.
- Following therapy with vinblastine sulfate, the nadir in white blood cell count may be expected to occur five to ten days after the last day of drug administration. Recovery of the white blood count is fairly rapid thereafter and is usually complete within another 7 to 14 days. With the smaller doses employed for maintenance therapy, leukopenia may not be a problem.
- Although the thrombocyte count ordinarily is not significantly lowered by therapy with vinblastine sulfate, patients whose bone marrow has been recently impaired by prior therapy with radiation or with other oncolytic drugs may show thrombocytopenia (less than 200,000 platelets/mm3). When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 200,000/mm3 is rarely encountered, even when vinblastine sulfate may be causing significant leukopenia. Rapid recovery from thrombocytopenia within a few days is the rule.
- The effect of vinblastine sulfate upon the red cell count and hemoglobin is usually insignificant when other therapy does not complicate the picture. It should be remembered, however, that patients with malignant disease may exhibit anemia even in the absence of any therapy.
## Nonclinical Toxicology
- Mutagenicity—Tests in Salmonella typhimurium and with the dominant lethal assay in mice failed to demonstrate mutagenicity. Sperm abnormalities have been noted in mice. Vinblastine sulfate has produced an increase in micronuclei formation in bone marrow cells of mice; however, since vinblastine sulfate inhibits mitotic spindle formation, it cannot be concluded that this is evidence of mutagenicity. Additional studies in mice demonstrated no reduction in fertility of males. Chromosomal translocations did occur in male mice. First-generation male offspring of these mice were not heterozygous translocation carriers.
- In vitro tests using hamster lung cells in culture have produced chromosomal changes, including chromatid breaks and exchanges, whereas tests using another type of hamster cell failed to demonstrate mutation. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients being treated with this drug.
- It is not clear from the literature how this drug affects synthesis of DNA and RNA. Some believe that there is no interference. Others believe that vinblastine interferes with nucleic acid metabolism but may not do so by direct effect but possibly as the result of biochemical disturbance in some other part of the molecular organization of the cell. No inhibition of RNA synthesis occurred in rat hepatoma cells exposed in culture to noncytotoxic levels of vinblastine. Conflicting results have been noted by others regarding interference with DNA synthesis.
- Carcinogenesis—There is no currently available evidence to indicate that vinblastine sulfate itself has been carcinogenic in humans since the inception of its clinical use in the late 1950’s. Patients treated for Hodgkin’s disease have developed leukemia following radiation therapy and administration of vinblastine sulfate in combination with other chemotherapy including agents known to intercalate with DNA. It is not known to what extent vinblastine sulfate may have contributed to the appearance of leukemia.
- Available data in rats and mice have failed to demonstrate clearly evidence of carcinogenesis when the animals were treated with the maximum tolerated dose and with one-half that dose for six months. *This testing system demonstrated that other agents were clearly carcinogenic, whereas vinblastine sulfate was in the group of drugs causing slightly increased or the same tumor incidence as controls in one study and 1.5 to two-fold increase in tumor incidence over controls in another study.
# Clinical Studies
There is limited information regarding Clinical Studies of vinblastine in the drug label.
# How Supplied
## Storage
- Store products in refrigerator 2° to 8°C (36° to 46°F) to assure extended stability.
- PROTECT FROM LIGHT. Retain vial in carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The patient should be warned to report immediately the appearance of sore throat, fever, chills or sore mouth. Advice should be given to avoid constipation, and the patient should be made aware that alopecia may occur and that jaw pain and pain in the organs containing tumor tissue may occur. The latter is thought possibly to result from swelling of tumor tissue during its response to treatment. Scalp hair will regrow to its pretreatment extent even with continued treatment with vinblastine sulfate. Nausea and vomiting, although not common, may occur. Any other serious medical event should be reported to the physician.
# Precautions with Alcohol
- Alcohol-vinblastine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Velban
# Look-Alike Drug Names
There is limited information regarding Vinblastine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vinblastine
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# Black Box Warning
# Overview
Vinblastine is an antineoplastic agent that is FDA approved for the treatment of palliative treatment of Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye staging system),Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated),Histiocytic lymphoma,Mycosis fungoides (advanced stages),Advanced carcinoma of the testis,Kaposi's sarcoma,
Letterer-Siwe disease (histiocytosis X). There is a Black Box Warning for this drug as shown here. Common adverse reactions include leukopenia,alopecia,constipation, anorexia, nausea, vomiting, abdominal pain, ileus, vesiculation of the mouth, pharyngitis, diarrhea,Hypertension, Malaise, bone pain, weakness, pain in tumor-containing tissue, dizziness, jaw pain, skin vesiculation,.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Vinblastine Sulfate Injection is indicated in the palliative treatment of the following:
- Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye staging system)
- Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated)
- Histiocytic lymphoma
- Mycosis fungoides (advanced stages)
- Advanced carcinoma of the testis
- Kaposi's sarcoma
- Letterer-Siwe disease (histiocytosis X)
- Choriocarcinoma resistant to other chemotherapeutic agents
- Carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy
Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose-limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine sulfate is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. Such combination therapy produces a greater percentage of response than does a single-agent regimen. These principles have been applied, for example, in the chemotherapy of Hodgkin’s disease.
- Vinblastine sulfate has been shown to be one of the most effective single agents for the treatment of Hodgkin’s disease. Advanced Hodgkin’s disease has also been successfully treated with several multiple-drug regimens that included vinblastine sulfate. Patients who had relapses after treatment with the MOPP program— mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, prednisone and procarbazine—have likewise responded to combination-drug therapy that included vinblastine sulfate. A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate instead of vincristine sulfate is an alternative therapy for previously untreated patients with advanced Hodgkin’s disease.
- Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma and choriocarcinoma) are sensitive to vinblastine sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine sulfate is administered six to eight hours prior to the administration of bleomycin; this schedule permits more cells to be arrested during metaphase, the stage of the cell cycle in which bleomycin is active.
- This preparation is for intravenous use only.
- WHEN DISPENSING VINBLASTINE SULFATE INJECTION IN OTHER THAN THE ORIGINAL CONTAINER, IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICH BEARS THE FOLLOWING STATEMENT: “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” . A syringe containing a specific dose must be labeled, using the auxiliary sticker provided to state: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.”
- Caution–It is extremely important that the intravenous needle or catheter be properly positioned before any vinblastine sultate is injected. Leakage into surrounding tissue during intravenous administration of vinblastine sulfate may cause considerable irritation. If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.
- There are variations in the depth of the leukopenic response that follows therapy with vinblastine sulfate. For this reason, it is
recommended that the drug be given no more frequently than once every seven days.
- It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m2 of body surface area (bsa). Thereafter, white blood cell counts should be made to determine the patient’s sensitivity to vinblastine sulfate.
- A simplified and conservative incremental approach to dosage at weekly intervals for adults may be outlined as follows:
- First dose ....................................... 3.7 mg/m2 bsa
- Second dose .................................. 5.5 mg/m2 bsa
- Third dose ...................................... 7.4 mg/m2 bsa
- Fourth dose .................................. 9.25 mg/m2 bsa
- Fifth dose ..................................... 11.1 mg/m2 bsa
- The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m2 bsa for adults is reached. The dose should not be increased after that dose which reduces the white cell count to approximately 3,000 cells/mm3. In some adults, 3.7 mg/m2 bsa may produce this leukopenia; other adults may require more than 11.1 mg/m2 bsa; and, very rarely, as much as 18.5 mg/m2 bsa may be necessary. For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m2 bsa.
- When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of one increment smaller than this should be administered at weekly intervals for maintenance. Thus, the patient is receiving the maximum dose that does not cause leukopenia. It should be emphasized that, even though seven days have elapsed, the next dose of vinblastine sulfate should not be given until the white cell count has returned to at least 4,000/mm3. In some cases, oncolytic activity may be encountered before leukopenic effect. When this occurs, there is no need to increase the size of subsequent doses.
## Off-Label Use and Dosage (Adult)
### Non–Guideline-Supported Use
- Carcinoma of bladder: MVAC regimen, vinBLAStine 3 mg/m(2) IV on days 2, 15, and 22; in combination with methotrexate 30 mg/m(2) on days 1, 15, and 22; doxorubicin 30 mg/m(2) on day 2; cisplatin 70 mg/m(2) IV on day 2; repeat every 28 days
Sternberg CN, de Mulder PH, Schornagel JH, Théodore C, Fossa SD, van Oosterom AT, et al. (2001). "Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924". J. Clin. Oncol. 19 (10): 2638–46. PMID 11352955..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Carcinoma of prostate: optimal dose and timing has not been defined in this setting; clinical trials have used doses of vinBLAStine of 4 mg/m(2) per wk IV for 6 wk, and then 2 wk off: optimal dose and timing has not been defined in this setting; clinical trials have used doses of vinBLAStine of 4 mg/m(2) per wk IV for 6 wk, and then 2 wk off Hudes G, Einhorn L, Ross E, Balsham A, Loehrer P, Ramsey H, et al. (1999). "Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial". J. Clin. Oncol. 17 (10): 3160–6. PMID 10506613.
- Germ cell tumor of ovary: optimal dose and timing of vinBLAStine has not been defined in this setting; PVB regimen has been used in clinical trials and consists of cisplatin 20 mg/m(2) IV) daily for 5 days, vinBLAStine 12 mg/m(2) IV push on day 1, and bleomycin 20 units/m(2) (maximum dose 30 units) IV push once weekly; administer every 3 weeks for 3 to 4 courses Williams SD, Birch R, Einhorn LH, Irwin L, Greco FA, Loehrer PJ (1987). "Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide". N. Engl. J. Med. 316 (23): 1435–40. doi:10.1056/NEJM198706043162302. PMID 2437455.
- VinBLAStine 0.1 milligram/kilogram was dissolved in 500 to 1000 milliliters of normal saline and infused intravenously over 6 to 8 hours.Ahn YS, Harrington WJ, Mylvaganam R, Allen LM, Pall LM (1984). "Slow infusion of vinca alkaloids in the treatment of idiopathic thrombocytopenic purpura". Ann. Intern. Med. 100 (2): 192–6. PMID 6537881.
- Metastatic malignant melanoma: optimal dose and timing have not been defined in this setting; CVD+IL-2I regimen has been used in a clinical trial and consists of cisplatin 20 mg/m(2) IV days 1 to 4, vinBLAStine 1.6 mg/m(2) IV days 1 to 5, dacarbazine 800 mg/m(2) IV day 1, IL-2 nine million units/m(2) continuous infusion days 1 to 4, interferon alfa 5 million units/m(2) subQ days 1 to 5, 7, 9, 11, and 13; repeat cycle every 21 days Legha SS, Ring S, Bedikian A, Plager C, Eton O, Buzaid AC, et al. (1996). "Treatment of metastatic melanoma with combined chemotherapy containing cisplatin, vinblastine and dacarbazine (CVD) and biotherapy using interleukin-2 and interferon-alpha". Ann. Oncol. 7 (8): 827–35. PMID 8922197.
- Non-small cell lung cancer: Adjuvant treatment, 4 mg/m(2) IV, in combination with various doses of cisplatin; administer once weekly until day 29 and then once every 2 wk after day 43 until the last dose of cisplatin Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J (2004). "Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer". N. Engl. J. Med. 350 (4): 351–60. doi:10.1056/NEJMoa031644. PMID 14736927.
- Renal cell carcinoma: 0.1 mg/kg IV every 3 weeks; in combination with interferon alfa-2a, 3 million units IM/subQ 3 times a week for 1 week then 18 million units 3 times a week thereafter has been used Pyrhönen S, Salminen E, Ruutu M, Lehtonen T, Nurmi M, Tammela T, et al. (1999). "Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer". J. Clin. Oncol. 17 (9): 2859–67. PMID 10561363.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Vinblastine Sulfate Injection is indicated in the palliative treatment of the following:
- Generalized Hodgkin’s disease (Stages III and IV, Ann Arbor modification of Rye staging system)
- Lymphocytic lymphoma (nodular and diffuse, poorly and well differentiated)
- Histiocytic lymphoma
- Mycosis fungoides (advanced stages)
- Advanced carcinoma of the testis
- Kaposi's sarcoma
- Letterer-Siwe disease (histiocytosis X)
- Choriocarcinoma resistant to other chemotherapeutic agents
- Carcinoma of the breast, unresponsive to appropriate endocrine surgery and hormonal therapy
Current principles of chemotherapy for many types of cancer include the concurrent administration of several antineoplastic agents. For enhanced therapeutic effect without additive toxicity, agents with different dose-limiting clinical toxicities and different mechanisms of action are generally selected. Therefore, although vinblastine sulfate is effective as a single agent in the aforementioned indications, it is usually administered in combination with other antineoplastic drugs. Such combination therapy produces a greater percentage of response than does a single-agent regimen. These principles have been applied, for example, in the chemotherapy of Hodgkin’s disease.
- Vinblastine sulfate has been shown to be one of the most effective single agents for the treatment of Hodgkin’s disease. Advanced Hodgkin’s disease has also been successfully treated with several multiple-drug regimens that included vinblastine sulfate. Patients who had relapses after treatment with the MOPP program— mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, prednisone and procarbazine—have likewise responded to combination-drug therapy that included vinblastine sulfate. A protocol using cyclophosphamide in place of nitrogen mustard and vinblastine sulfate instead of vincristine sulfate is an alternative therapy for previously untreated patients with advanced Hodgkin’s disease.
- Advanced testicular germinal-cell cancers (embryonal carcinoma, teratocarcinoma and choriocarcinoma) are sensitive to vinblastine sulfate alone, but better clinical results are achieved when vinblastine sulfate is administered concomitantly with other antineoplastic agents. The effect of bleomycin is significantly enhanced if vinblastine sulfate is administered six to eight hours prior to the administration of bleomycin; this schedule permits more cells to be arrested during metaphase, the stage of the cell cycle in which bleomycin is active.
- A review of published literature from 1993 to 1995 showed that initial doses of vinblastine sulfate in pediatric patients varied depending on the schedule used and whether vinblastine sulfate was administered as a single agent or incorporated within a particular chemotherapeutic regimen. As a single agent for Letterer-Siwe disease (histiocytosis X), the initial dose of vinblastine sulfate was reported as 6.5 mg/m2. When vinblastine sulfate was used in combination with other chemotherapeutic agents for the treatment of Hodgkin’s disease, the initial dose was reported as 6 mg/m2. For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m2 in a combination regimen. Dose modifications should be guided by hematologic tolerance.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
- Vinblastine sulfate is contraindicated in patients who have significant granulocytopenia unless this is a result of the disease being treated. It should not be used in the presence of bacterial infections. Such infections must be brought under control prior to the initiation of therapy with vinblastine sulfate.
# Warnings
- This preparation is for intravenous use only. It should be administered by individuals experienced in the administration of vinblastine sulfate. The intrathecal administration of vinblastine sulfate usually results in death. Syringes containing this product should be labeled, using the auxiliary sticker provided, to state ‘‘FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES. ’’
- Extemporaneously prepared syringes containing this product must be packaged in an overwrap which is labeled ‘‘DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION. FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.’’
- After inadvertent intrathecal administration of vinca alkaloids, immediate neurosurgical intervention is required in order to prevent ascending paralysis leading to death. In a very small number of patients, life-threatening paralysis and subsequent death was averted but resulted in devastating neurological sequelae, with limited recovery afterwards.
- There are no published cases of survival following intrathecal administration of vinblastine sulfate to base treatment on. However, based on the published management of survival cases involving the related vinca alkaloid vincristine sulfate1-3, if vinblastine sulfate is mistakenly given by the intrathecal route, the following treatment should be initiated immediately after the injection:
- Removal of as much CSF as is safely possible through the lumbar access.
- Insertion of an epidural catheter into the subarachnoid space via the intervertebral space above initial lumbar access and CSF irrigation with lactated Ringer’s solution. Fresh frozen plasma should be requested and, when available, 25 mL should be added to every 1 liter of lactated Ringer’s solution.
- Insertion of an intraventricular drain or catheter by a neurosurgeon and continuation of CSF irrigation with fluid removal through the lumbar access connected to a closed drainage system. Lactated Ringer’s solution should be given by continuous infusion at 150 mL/hour, or at a rate of 75 mL/hour when fresh frozen plasma has been added as above.
- The rate of infusion should be adjusted to maintain a spinal fluid protein level of 150 mg/dL.
- The following measures have also been used in addition but may not be essential:
- Glutamic acid, 10 grams, has been given intravenously over 24 hours, followed by 500 mg three times daily by mouth for 1 month.
- Folinic acid has been administered intravenously as a 100 mg bolus and then infused at a rate of 25 mg/hour for 24 hours, then bolus doses of 25 mg every 6 hours for 1 week. Pyridoxine has been given at a dose of 50 mg every 8 hours by intravenous infusion over 30 minutes. Their roles in the reduction of neurotoxicity are unclear.
### Precautions
- Toxicity may be enhanced in the presence of hepatic insufficiency.
- If leukopenia with less than 2,000 white blood cells/mm3 occurs following a dose of vinblastine sulfate, the patient should be watched carefully for evidence of infection until the white blood cell count has returned to a safe level.
- When cachexia or ulcerated areas of the skin surface are present, there may be a more profound leukopenic response to the drug; therefore, its use should be avoided in older persons suffering from either of these conditions.
- In patients with malignant-cell infiltration of the bone marrow, the leukocyte and platelet counts have sometimes fallen precipitously after moderate doses of vinblastine sulfate. Further use of the drug in such patients is inadvisable.
- Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids. These reactions have been encountered most frequently when the vinca alkaloid was used in combination with mitomycin-C and may require aggressive treatment, particularly when there is pre-existing pulmonary dysfunction. The onset may be within minutes or several hours after the vinca is injected and may occur up to two weeks following a dose of mitomycin. Progressive dyspnea requiring chronic therapy may occur. Vinblastine should not be readministered.
- Care should be recommended in patients with ischemic cardiac disease.
- The use of small amounts of vinblastine sulfate daily for long periods is not advised, even though the resulting total weekly dosage may be similar to that recommended. Little or no added therapeutic effect has been demonstrated when such regimens have been used. Strict adherence to the recommended dosage schedule is very important. When amounts equal to several times the recommended weekly dosage were given in seven daily installments for long periods, convulsions, severe and permanent central nervous system damage, and even death occurred.
- Care must be taken to avoid contamination of the eye with concentrations of vinblastine sulfate used clinically. If accidental contamination occurs, severe irritation (or, if the drug was delivered under pressure, even corneal ulceration) may result. The eye should be washed with water immediately and thoroughly.
# Adverse Reactions
## Clinical Trials Experience
- Prior to the use of the drug, patients should be advised of the possibility of untoward symptoms.
- In general, the incidence of adverse reactions attending the use of vinblastine sulfate appears to be related to the size of the dose employed. With the exception of epilation, leukopenia and neurologic side effects, adverse reactions generally have not persisted for longer than 24 hours. Neurologic side effects are not common; but when they do occur, they often last for more than 24 hours. Leukopenia, the most common adverse reaction, is usually the dose-limiting factor.
- The following are manifestations that have been reported as adverse reactions, in decreasing order of frequency. The most common adverse reactions are underlined:
- Leukopenia (granulocytopenia), anemia, thrombocytopenia (myelosuppression).
- Alopecia is common. A single case of light sensitivity associated with this product has been reported.
- Constipation, anorexia, nausea, vomiting, abdominal pain, ileus, vesiculation of the mouth, pharyngitis, diarrhea, hemorrhagic enterocolitis, bleeding from an old peptic ulcer and rectal bleeding.
- Numbness of digits (paresthesias), loss of deep tendon reflexes, peripheral neuritis, mental depression, headache, convulsions.
- Treatment with vinca alkaloids has resulted rarely in both vestibular and auditory damage to the eighth cranial nerve.
- Manifestations include partial or total deafness which may be temporary or permanent, and difficulties with balance including dizziness, nystagmus and vertigo. Particular caution is warranted when vinblastine sulfate is used in combination with other agents known to be ototoxic such as the platinum-containing oncolytics.
- Hypertension—Cardiac effects such as myocardial infarction, angina pectoris and transient abnormalities of ECG related to coronary ischemia have been reported very rarely. Cases of unexpected myocardial infarction and cerebrovascular accidents have occurred in patients undergoing combination chemotherapy with vinblastine, bleomycin and cisplatin. Raynaud’s phenomenon has also been reported with this combination.
- Malaise, bone pain, weakness, pain in tumor-containing tissue, dizziness, jaw pain, skin vesiculation, hypertension, Raynaud’s phenomenon when patients are being treated with vinblastine sulfate in combination with bleomycin and cis-platinum for testicular cancer. The syndrome of inappropriate secretion of antidiuretic hormone has occurred with higher than recommended doses.
- Nausea and vomiting usually may be controlled with ease by antiemetic agents. When epilation develops, it frequently is not total; and, in some cases, hair regrows while maintenance therapy continues.
- Extravasation during intravenous injection may lead to cellulitis and phlebitis. If the amount of extravasation is great, sloughing may occur.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of vinblastine in the drug label.
# Drug Interactions
- The simultaneous oral or intravenous administration of phenytoin and antineoplastic chemotherapy combinations that included vinblastine sulfate has been reported to have reduced blood levels of the anticonvulsant and to have increased seizure activity. Dosage adjustment should be based on serial blood level monitoring. The contribution of vinblastine sulfate to this interaction is not certain. The interaction may result from either reduced absorption of phenytoin or an increase in the rate of its metabolism and elimination.
- Caution should be exercised in patients concurrently taking drugs known to inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily, or in patients with hepatic dysfunction. Concurrent administration of vinblastine sulfate with an inhibitor of this metabolic pathway may cause an earlier onset and/or an increased severity of side effects. Enhanced toxicity has been reported in patients receiving concomitant erythromycin
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Caution is necessary with the administration of all oncolytic drugs during pregnancy. Information on the use of vinblastine sulfate during human pregnancy is very limited. Animal studies with vinblastine sulfate suggest that teratogenic effects may occur. Vinblastine sulfate can cause fetal harm when administered to a pregnant woman. Laboratory animals given this drug early in pregnancy suffer resorption of the conceptus; surviving fetuses demonstrate gross deformities. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
- Aspermia has been reported in man. Animal studies show metaphase arrest and degenerative changes in germ cells.
- Leukopenia (granulocytopenia) may reach dangerously low levels following administration of the higher recommended doses. It is therefore important to follow the dosage technique. Stomatitis and neurologic toxicity, although not common or permanent, can be disabling.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of vinblastine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of vinblastine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from vinblastine sulfate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
There is no FDA guidance on the use of vinblastine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of vinblastine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of vinblastine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of vinblastine with respect to specific racial populations.
### Renal Impairment
- A reduction of 50% in the dose of vinblastine sulfate is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL. Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.
- The duration of maintenance therapy varies according to the disease being treated and the combination of antineoplastic agents being used. There are differences of opinion regarding the duration of maintenance therapy with the same protocol for a particular disease; for example, various durations have been used with the MOPP program in treating Hodgkin’s disease. Prolonged chemotherapy for maintaining remissions involves several risks, among which are life-threatening infectious diseases, sterility and possibly the appearance of other cancers through suppression of immune surveillance.
- In some disorders, survival following complete remission may not be as prolonged as that achieved with shorter periods of maintenance therapy. On the other hand, failure to provide maintenance therapy in some patients may lead to unnecessary relapse; complete remissions in patients with testicular cancer, unless maintained for at least two years, often result in early relapse.
- The dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous infusion or directly into a vein. The latter procedure is readily adaptable to outpatient therapy. In either case, the injection may be completed in about one minute. If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine sulfate is spilled extra-vascularly, cellulitis and/or phlebitis will not occur. To minimize further the possibility of extra vascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal of the needle. The dose should not be diluted in large volumes of diluent (i.e., 100 to 250 mL) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), since this frequently results in irritation of the vein and increases the chance of extravasation.
- Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis or varicosity.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Procedures for proper handling and disposal of anti-cancer drugs should be considered. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate
### Hepatic Impairment
There is no FDA guidance on the use of vinblastine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of vinblastine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of vinblastine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of vinblastine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of vinblastine in the drug label.
# Overdosage
- Side effects following the use of vinblastine sulfate are dose related. Therefore, following administration of more than the recommended dose, patients can be expected to experience these effects in an exaggerated fashion.There is no specific antidote. In addition, neurotoxicity similar to that with vincristine sulfate may be observed. Since the major route of excretion may be through the biliary system, toxicity from this drug may be increased when there is hepatic insufficiency.
- To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. . *In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs and unusual drug kinetics in your patient. Overdoses of vinblastine sulfate have been reported rarely. The following is provided to serve as a guide should such an overdose be encountered.
- Supportive care should include the following: (1) prevention of side effects that result from the syndrome of inappropriate secretion of antidiuretic hormone (this would include restriction of the volume of daily fluid intake to that of the urine output plus insensible loss and perhaps the administration of a diuretic affecting the function of the loop of Henle and the distal tubule); (2) administration of an anticonvulsant; (3) prevention of ileus: (4) monitoring the cardiovascular system; and (5) determining daily blood counts for guidance in transfusion requirements and assessing the risk of infection. The major effect of excessive doses of vinblastine sulfate will be myelosuppression, which may be life-threatening. There is no information regarding the effectiveness of dialysis nor of cholestyramine for the treatment of overdosage.
- Vinblastine sulfate in the dry state is irregularly and unpredictably absorbed from the gastrointestinal tract following oral administration. Absorption of the solution has not been studied. If vinblastine is swallowed, activated charcoal in a water slurry may be given by mouth along with a cathartic. The use of cholestyramine in this situation has not been reported.
- Symptoms of overdose will appear when greater-than-recommended doses are given. Any dose of vinblastine sulfate that results in elimination of platelets and neutrophils from blood and marrow and their precursors from marrow should be considered life-threatening. The exact dose that will do this in all patients is unknown. Overdoses occurring during prolonged consecutive-day infusions may be more toxic than the same total dose given by rapid intravenous injection. The intravenous median lethal dose in mice is 10 mg/kg body weight; in rats, it is 2.9 mg/kg. The oral median lethal dose in rats is 7 mg/kg.
- Protect the patient’s airway and support ventilation and perfusion.
- Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc.
- Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying if the drug has been swallowed.
- Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.
# Pharmacology
## Mechanism of Action
- Experimental data indicate that the action of vinblastine sulfate is different from that of other recognized antineoplastic agents. Tissue-culture studies suggest an interference with metabolic pathways of amino acids leading from glutamic acid to the citric acid cycle and to urea. In vivo experiments tend to confirm the in vitro results. A number of studies in vitro and in vivo have demonstrated that vinblastine sulfate produces a stathmokinetic effect and various atypical mitotic figures. The therapeutic responses, however, are not fully explained by the cytologic changes, since these changes are sometimes observed clinically and experimentally in the absence of any oncolytic effects.
- Reversal of the antitumor effect of vinblastine sulfate by glutamic acid or tryptophan has been observed. In addition, glutamic acid and aspartic acid have protected mice from lethal doses of vinblastine sulfate. Aspartic acid was relatively ineffective in reversing the antitumor effect.
- Other studies indicate that vinblastine sulfate has an effect on cell-energy production required for mitosis and interferes with nucleic acid synthesis. The mechanism of action of vinblastine has been related to the inhibition of microtubule formation in the mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage.
## Structure
- Vinblastine sulfate is the salt of an alkaloid extracted from Vinca rosea Linn., a common flowering herb known as the periwinkle (more properly known as Catharanthus roseus G. Don). Previously, the generic name was vincaleukoblastine, abbreviated VLB. It is a stathmokinetic oncolytic agent. When treated in vitro with this preparation, growing cells are arrested in metaphase.
- Chemical and physical evidence indicate that vinblastine sulfate is a dimeric alkaloid containing both indole and dihydroindole moieties.
- The accompanying structural formula has been proposed.
- Each mL contains: Vinblastine sulfate 1 mg; sodium chloride 9 mg; benzyl alcohol 0.9% (v/v) as a preservative; Water for Injection q.s. (pH 3.5 to 5.0).
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of vinblastine in the drug label.
## Pharmacokinetics
- Pharmacokinetic studies in patients with cancer have shown a triphasic serum decay pattern following rapid intravenous injection. The initial, middle and terminal half-lives are 3.7 minutes, 1.6 hours and 24.8 hours, respectively. The volume of the central compartment is 70% of body weight, probably reflecting very rapid tissue binding to formed elements of the blood. Extensive reversible tissue binding occurs. Low body stores are present at 48 and 72 hours after injection.Since the major route of excretion may be through the biliary system, toxicity from this drug may be in creased when there is hepatic excretory insufficiency.The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP 3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes such as erythromycin. Enhanced toxicity has been reported in patients receiving concomitant erythromycin . Following injection of tritiated vinblastine in the human cancer patient, 10% of the radioactivity was found in the feces and 14% in the urine; the remaining activity was not accounted for. Similar studies in dogs demonstrated that, over nine days, 30 to 36% of radioactivity was found in the bile and 12 to 17% in the urine. A similar study in the rat demonstrated that the highest concentrations of radioactivity were found in the lung, liver, spleen and kidney two hours after injection.
- Hematologic Effects
- Clinically, leukopenia is an expected effect of vinblastine sulfate, and the level of the leukocyte count is an important guide to therapy with this drug. In general, the larger the dose employed, the more profound and longer lasting the leukopenia will be. The fact that the white blood cell count returns to normal levels after drug-induced leukopenia is an indication that the white cell-producing mechanism is not permanently depressed. Usually, the white count has completely returned to normal after the virtual disappearance of white cells from the peripheral blood.
- Following therapy with vinblastine sulfate, the nadir in white blood cell count may be expected to occur five to ten days after the last day of drug administration. Recovery of the white blood count is fairly rapid thereafter and is usually complete within another 7 to 14 days. With the smaller doses employed for maintenance therapy, leukopenia may not be a problem.
- Although the thrombocyte count ordinarily is not significantly lowered by therapy with vinblastine sulfate, patients whose bone marrow has been recently impaired by prior therapy with radiation or with other oncolytic drugs may show thrombocytopenia (less than 200,000 platelets/mm3). When other chemotherapy or radiation has not been employed previously, thrombocyte reduction below the level of 200,000/mm3 is rarely encountered, even when vinblastine sulfate may be causing significant leukopenia. Rapid recovery from thrombocytopenia within a few days is the rule.
- The effect of vinblastine sulfate upon the red cell count and hemoglobin is usually insignificant when other therapy does not complicate the picture. It should be remembered, however, that patients with malignant disease may exhibit anemia even in the absence of any therapy.
## Nonclinical Toxicology
- Mutagenicity—Tests in Salmonella typhimurium and with the dominant lethal assay in mice failed to demonstrate mutagenicity. Sperm abnormalities have been noted in mice. Vinblastine sulfate has produced an increase in micronuclei formation in bone marrow cells of mice; however, since vinblastine sulfate inhibits mitotic spindle formation, it cannot be concluded that this is evidence of mutagenicity. Additional studies in mice demonstrated no reduction in fertility of males. Chromosomal translocations did occur in male mice. First-generation male offspring of these mice were not heterozygous translocation carriers.
- In vitro tests using hamster lung cells in culture have produced chromosomal changes, including chromatid breaks and exchanges, whereas tests using another type of hamster cell failed to demonstrate mutation. Breaks and aberrations were not observed on chromosome analysis of marrow cells from patients being treated with this drug.
- It is not clear from the literature how this drug affects synthesis of DNA and RNA. Some believe that there is no interference. Others believe that vinblastine interferes with nucleic acid metabolism but may not do so by direct effect but possibly as the result of biochemical disturbance in some other part of the molecular organization of the cell. No inhibition of RNA synthesis occurred in rat hepatoma cells exposed in culture to noncytotoxic levels of vinblastine. Conflicting results have been noted by others regarding interference with DNA synthesis.
- Carcinogenesis—There is no currently available evidence to indicate that vinblastine sulfate itself has been carcinogenic in humans since the inception of its clinical use in the late 1950’s. Patients treated for Hodgkin’s disease have developed leukemia following radiation therapy and administration of vinblastine sulfate in combination with other chemotherapy including agents known to intercalate with DNA. It is not known to what extent vinblastine sulfate may have contributed to the appearance of leukemia.
- Available data in rats and mice have failed to demonstrate clearly evidence of carcinogenesis when the animals were treated with the maximum tolerated dose and with one-half that dose for six months. *This testing system demonstrated that other agents were clearly carcinogenic, whereas vinblastine sulfate was in the group of drugs causing slightly increased or the same tumor incidence as controls in one study and 1.5 to two-fold increase in tumor incidence over controls in another study.
# Clinical Studies
There is limited information regarding Clinical Studies of vinblastine in the drug label.
# How Supplied
-
## Storage
- Store products in refrigerator 2° to 8°C (36° to 46°F) to assure extended stability.
- PROTECT FROM LIGHT. Retain vial in carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- The patient should be warned to report immediately the appearance of sore throat, fever, chills or sore mouth. Advice should be given to avoid constipation, and the patient should be made aware that alopecia may occur and that jaw pain and pain in the organs containing tumor tissue may occur. The latter is thought possibly to result from swelling of tumor tissue during its response to treatment. Scalp hair will regrow to its pretreatment extent even with continued treatment with vinblastine sulfate. Nausea and vomiting, although not common, may occur. Any other serious medical event should be reported to the physician.
# Precautions with Alcohol
- Alcohol-vinblastine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Velban
# Look-Alike Drug Names
There is limited information regarding Vinblastine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Vinblastine | |
16b46e9cae5e8647c005c9a78733fcbac34f18fb | wikidoc | Vinca minor | Vinca minor
Vinca minor (Lesser Periwinkle) is a plant native to central and southern Europe, from Portugal and France north to the Netherlands and the Baltic States, and east to the Caucasus, and also in southwestern Asia in Turkey.
It is a trailing subshrub, spreading along the ground and rooting along the stems to form large clonal colonies and occasionally scrambling up to 40 cm high but never twining or climbing. The leaves are evergreen, opposite, 2-4.5 cm long and 1-2.5 cm broad, glossy dark green with a leathery texture and an entire margin. The flowers are solitary in the leaf axils and are produced mainly from early spring to mid summer but with a few flowers still produced into the autumn; they are violet-purple (pale purple or white in some cultivated selections), 2-3 cm diameter, with a five-lobed corolla. The fruit is a pair of follicles 2.5 cm long, containing numerous seeds.
The closely related species Vinca major is similar but larger in all parts, and with relatively broader leaves with a hairy margin.
## Cultivation and uses
The species is commonly grown as a groundcover in temperate gardens for its evergreen foliage, spring and summer flowers, ease of culture, and dense habit that smothers most weeds. The species has few pests or diseases outside it native range and is widely naturalised and classified as an invasive species in parts of North America . There are numerous cultivars, with different flower colours and variegated foliage, including 'Argenteovariegata' (white leaf edges), 'Aureovariegata' (yellow leaf edges), 'Gertrude Jekyll' (white flowers), and 'Plena' (double flowers).
Other vernacular names used in cultivation include Small Periwinkle, Common Periwinkle, and sometimes in the United States, Myrtle or Creeping Myrtle (as a result of confusion with the unrelated myrtles ).
- Ethnomedically, the dried leaves, aerial parts, and in some cases the entire plant of Vinca, are used to enhance blood circulation, including that of the brain, enhance metabolism in the brain, and to treat cardiovascular disorders.
Vincamine is the pharmaceutical molecule responsible for Vinca's nootropic activity.
# References and external links
- Flora Europaea: Vinca minor distribution
- Morphology and ecology of Vinca minor (in Spanish)
- Borealforest: Vinca minor
- Vinca minor (from Ohio State University's Pocket Gardener)
- Common Periwinkle (as an invasive species; includes photos)
- Blamey, M., & Grey-Wilson, C. (1989). Flora of Britain and Northern Europe. Hodder & Stoughton.
- Huxley, A., ed. (1992). New RHS Dictionary of Gardening 4: 665. Macmillan.
cs:Barvínek menší
da:Lille Singrøn
de:Kleines Immergrün
fy:Frisselgrien
it:Vinca minor
lt:Mažoji žiemė
hu:Kis meténg
nl:Kleine maagdenpalm
uk:Барвінок малий | Vinca minor
Vinca minor (Lesser Periwinkle) is a plant native to central and southern Europe, from Portugal and France north to the Netherlands and the Baltic States, and east to the Caucasus, and also in southwestern Asia in Turkey.
It is a trailing subshrub, spreading along the ground and rooting along the stems to form large clonal colonies and occasionally scrambling up to 40 cm high but never twining or climbing. The leaves are evergreen, opposite, 2-4.5 cm long and 1-2.5 cm broad, glossy dark green with a leathery texture and an entire margin. The flowers are solitary in the leaf axils and are produced mainly from early spring to mid summer but with a few flowers still produced into the autumn; they are violet-purple (pale purple or white in some cultivated selections), 2-3 cm diameter, with a five-lobed corolla. The fruit is a pair of follicles 2.5 cm long, containing numerous seeds.
The closely related species Vinca major is similar but larger in all parts, and with relatively broader leaves with a hairy margin.
## Cultivation and uses
The species is commonly grown as a groundcover in temperate gardens for its evergreen foliage, spring and summer flowers, ease of culture, and dense habit that smothers most weeds. The species has few pests or diseases outside it native range and is widely naturalised and classified as an invasive species in parts of North America [1]. There are numerous cultivars, with different flower colours and variegated foliage, including 'Argenteovariegata' (white leaf edges), 'Aureovariegata' (yellow leaf edges), 'Gertrude Jekyll' (white flowers), and 'Plena' (double flowers).
Other vernacular names used in cultivation include Small Periwinkle, Common Periwinkle, and sometimes in the United States, Myrtle or Creeping Myrtle (as a result of confusion with the unrelated myrtles [2]).
- Ethnomedically, the dried leaves, aerial parts, and in some cases the entire plant of Vinca, are used to enhance blood circulation, including that of the brain, enhance metabolism in the brain, and to treat cardiovascular disorders.
Vincamine is the pharmaceutical molecule responsible for Vinca's nootropic activity.
# References and external links
- Flora Europaea: Vinca minor distribution
- Morphology and ecology of Vinca minor (in Spanish)
- Borealforest: Vinca minor
- Vinca minor (from Ohio State University's Pocket Gardener)
- Common Periwinkle (as an invasive species; includes photos)
- Blamey, M., & Grey-Wilson, C. (1989). Flora of Britain and Northern Europe. Hodder & Stoughton.
- Huxley, A., ed. (1992). New RHS Dictionary of Gardening 4: 665. Macmillan.
cs:Barvínek menší
da:Lille Singrøn
de:Kleines Immergrün
fy:Frisselgrien
it:Vinca minor
lt:Mažoji žiemė
hu:Kis meténg
nl:Kleine maagdenpalm
uk:Барвінок малий
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Vinca_minor | |
56aad052e109a19665ca034f5dadd59142eec850 | wikidoc | Vinpocetine | Vinpocetine
# Overview
Vinpocetine (brand names: Cavinton, Intelectol; chemical name: ethyl apovincaminate) is a semisynthetic derivative of the vinca alkaloid vincamine (sometimes described as "a synthetic ethyl ester of apovincamine"), an extract from the lesser periwinkle plant. Vinpocetine was first isolated from the plant in 1975 by the Hungarian chemist Csaba Szántay. The mass production of the synthetic drug was started in 1978 by the Hungarian pharmaceutical company Richter Gedeon.
Vinpocetine is reported to have cerebral blood-flow enhancing and neuroprotective effects, and is used as a drug in Eastern Europe for the treatment of cerebrovascular disorders and age-related memory impairment.
Vinpocetine is not approved in the United States for pharmaceutical use, but it can be sold as a dietary supplement. Vinpocetine is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory and cerebral metabolism. Vinpocetine has been identified as a potent anti-inflammatory agent that might have a potential role in the treatment of Parkinson's disease and Alzheimer's disease.
# Controlled clinical trials
As of 2003 only three controlled clinical trials had tested "older adults with memory problems". However, a 2003 Cochrane review determined that the results were inconclusive.
Prior to 2003, a different study from 1985 had tested young, healthy adults, but this study had 12 subjects and used a short treatment period.
# Use as a vasodilator
Vinpocetine is widely used in the body building community as a vasodilator. Although no studies have been conducted on the effectiveness of vinpocetine on performance enhancement during exercise, both beneficial and adverse effects have been reported on body building forums.
# Anticonvulsant potential
Kindling models in rats has shown Vinpocetine to exhibit anticonvulsant properties, the most pronounced anticonvulsant effects were observed in Pentylenetetrazole (PTZ)-kindled rats although there was also an effect on amygdala-kindled and neocortically-kindled rats. Vinpocetine has also been shown to abolished Glu release after in vivo exposure to 4-aminopyridine (4-AP) which suggests an important mechanism for vinpocetine anticonvulsant potential.
# Anti-inflammatory action
Vinpocetine has been identified as a novel anti-inflammatory agent. Vinpocetine inhibits the up-regulation of NF-κB by TNFα in various cell tests. Reverse transcription polymerase chain reaction also shows that it reduced the TNFα-induced expression of the mRNA of proinflammatory molecules such as interleukin-1 beta, monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). In mice, vinpocetine reduced lipopolysaccharide inoculation induced polymorphonuclear neutrophil infiltration into the lung. Neuroinflammatory processes can result in neuronal death in Parkinson's disease (PD) and Alzheimer's disease (AD). It has been suggested that "it would be interesting to test whether vinpocetine’s antiinflammatory properties would have a protective effect in models of neurodegenerative conditions such as AD and PD."
# Mechanism of action
Vinpocetine has been shown to selectively inhibit voltage-sensitive Na+ channels, resulting in a dose-dependent decrease in evoked extracellular Ca+ ions in striatal nerve endings. The Na+ channel inhibiting properties of vinpocetine are thought to contribute to a general neuroprotective effect through blockade of excitotoxicity and attenuation of neuronal damage induced by cerebral ischemia/reperfusion.
Vinpocetine is also a phosphodiesterase (PDE) type-1 inhibitor, (with an IC50 of approximately 10−5 M.) leading to increases in intracellular levels of cyclic guanosine 3'5'-monophosphate (cGMP), an action that causes the vasorelaxant effects of vinpocetine on cerebral smooth muscle tissue.
Independent of vinpocetine's action on PDE, vinpocetine inhibits IKK preventing IκB degradation and the following translocation of NF-κB to the cell nucleus.
Increases in neuronal levels of DOPAC, a metabolic breakdown product of dopamine, have been shown to occur in striatal isolated nerve endings as a result of exposure to vinpocetine. Such an effect is consistent with the biogenic pharmacology of reserpine, a structural relative of vinpocetine, which depletes catecholamine levels and causes depression as a side effect of the cardiovascular and anti-psychotic effects. However, this effect tends to be reversible upon cessation of Vinpocetine administration, with full remission typically occurring within 3–4 weeks.
# Side effects
Vinpocetine is generally well-tolerated in humans. No serious side effects have thus far been noted in clinical trials, although none of these trials were long-term. Some users have reported headaches, especially at doses above 15 milligrams per day, as well as occasional upset stomach. Adverse drug-herb interactions have not been prevalent, and vinpocetine appears safe to take with other medications, including diabetes drugs, as well as blood thinners like Coumadin. However, it should be carefully noted that the safety of vinpocetine in pregnant women has not been evaluated. Vinpocetine has been implicated in one case to induce agranulocytosis, a condition in which granulocytes are markedly decreased. Some people have anecdotally noted that their continued use of vinpocetine reduces immune function. Commission E warned that vinpocetine reduced immune function and could cause apoptosis (cellular death) in the long term. | Vinpocetine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Vinpocetine (brand names: Cavinton, Intelectol; chemical name: ethyl apovincaminate) is a semisynthetic derivative of the vinca alkaloid vincamine (sometimes described as "a synthetic ethyl ester of apovincamine"),[1] an extract from the lesser periwinkle plant. Vinpocetine was first isolated from the plant in 1975 by the Hungarian chemist Csaba Szántay. The mass production of the synthetic drug was started in 1978 by the Hungarian pharmaceutical company Richter Gedeon.
Vinpocetine is reported to have cerebral blood-flow enhancing[2] and neuroprotective effects,[3] and is used as a drug in Eastern Europe for the treatment of cerebrovascular disorders and age-related memory impairment.[4]
Vinpocetine is not approved in the United States for pharmaceutical use, but it can be sold as a dietary supplement. Vinpocetine is widely marketed as a supplement for vasodilation and as a nootropic for the improvement of memory and cerebral metabolism. Vinpocetine has been identified as a potent anti-inflammatory agent that might have a potential role in the treatment of Parkinson's disease and Alzheimer's disease.[5][6]
# Controlled clinical trials
As of 2003 only three controlled clinical trials had tested "older adults with memory problems".[7] However, a 2003 Cochrane review determined that the results were inconclusive.[8]
Prior to 2003, a different study from 1985[9] had tested young, healthy adults, but this study had 12 subjects and used a short treatment period.[7]
# Use as a vasodilator
Vinpocetine is widely used in the body building community as a vasodilator. Although no studies have been conducted on the effectiveness of vinpocetine on performance enhancement during exercise, both beneficial and adverse effects have been reported on body building forums.[citation needed]
# Anticonvulsant potential
Kindling models in rats has shown Vinpocetine to exhibit anticonvulsant properties, the most pronounced anticonvulsant effects were observed in Pentylenetetrazole (PTZ)-kindled rats although there was also an effect on amygdala-kindled and neocortically-kindled rats.[10] Vinpocetine has also been shown to abolished [3H]Glu release after in vivo exposure to 4-aminopyridine (4-AP) which suggests an important mechanism for vinpocetine anticonvulsant potential.[11]
# Anti-inflammatory action
Vinpocetine has been identified as a novel anti-inflammatory agent.[5][6] Vinpocetine inhibits the up-regulation of NF-κB by TNFα in various cell tests. Reverse transcription polymerase chain reaction also shows that it reduced the TNFα-induced expression of the mRNA of proinflammatory molecules such as interleukin-1 beta, monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1). In mice, vinpocetine reduced lipopolysaccharide inoculation induced polymorphonuclear neutrophil infiltration into the lung.[5][6] Neuroinflammatory processes can result in neuronal death in Parkinson's disease (PD) and Alzheimer's disease (AD). It has been suggested that "it would be interesting to test whether vinpocetine’s antiinflammatory properties would have a protective effect in models of neurodegenerative conditions such as AD and PD."[6]
# Mechanism of action
Vinpocetine has been shown to selectively inhibit voltage-sensitive Na+ channels, resulting in a dose-dependent decrease in evoked extracellular Ca+ ions in striatal nerve endings.[12] The Na+ channel inhibiting properties of vinpocetine are thought to contribute to a general neuroprotective effect through blockade of excitotoxicity and attenuation of neuronal damage induced by cerebral ischemia/reperfusion.[13]
Vinpocetine is also a phosphodiesterase (PDE) type-1 inhibitor,[14] (with an IC50 of approximately 10−5 M.) leading to increases in intracellular levels of cyclic guanosine 3'5'-monophosphate (cGMP), an action that causes the vasorelaxant effects of vinpocetine on cerebral smooth muscle tissue.[15][16]
Independent of vinpocetine's action on PDE, vinpocetine inhibits IKK preventing IκB degradation and the following translocation of NF-κB to the cell nucleus.[5][6]
Increases in neuronal levels of DOPAC, a metabolic breakdown product of dopamine, have been shown to occur in striatal isolated nerve endings as a result of exposure to vinpocetine.[17] Such an effect is consistent with the biogenic pharmacology of reserpine, a structural relative of vinpocetine, which depletes catecholamine levels and causes depression as a side effect of the cardiovascular and anti-psychotic effects.[17] However, this effect tends to be reversible upon cessation of Vinpocetine administration, with full remission typically occurring within 3–4 weeks.
# Side effects
Vinpocetine is generally well-tolerated in humans.[18] No serious side effects have thus far been noted in clinical trials,[19] although none of these trials were long-term.[8] Some users have reported headaches, especially at doses above 15 milligrams per day, as well as occasional upset stomach. Adverse drug-herb interactions have not been prevalent, and vinpocetine appears safe to take with other medications, including diabetes drugs, as well as blood thinners like Coumadin.[18] However, it should be carefully noted that the safety of vinpocetine in pregnant women has not been evaluated. Vinpocetine has been implicated in one case to induce agranulocytosis,[20] a condition in which granulocytes are markedly decreased. Some people have anecdotally noted that their continued use of vinpocetine reduces immune function. Commission E warned that vinpocetine reduced immune function and could cause apoptosis (cellular death) in the long term.[21] | https://www.wikidoc.org/index.php/Vinpocetine | |
734c7f155b379cde5bc2f88e2f6eda10143d0ca0 | wikidoc | Vintafolide | Vintafolide
# Overview
Vintafolide is an investigational targeted cancer therapeutic currently under development by Endocyte and Merck & Co. It is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is overexpressed on certain cancers, such as ovarian cancer, and a potent chemotherapy drug, vinblastine. It is being developed with a companion imaging agent, etarfolatide, that identifies patients that express the folate receptor and thus would likely respond to the treatment with vintafolide. A Phase 3 study evaluating vintafolide for the treatment of platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study(TARGET trial) in non-small-cell lung carcinoma (NSCLC) are ongoing. Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.
A Marketing Authorization Application (MAA) filing for vintafolide and etarfolatide for the treatment of patients with folate receptor-positive platinum-resistant ovarian cancer in combination with doxorubicin, pegylated liposomal doxorubicin (PLD), has been accepted by the European Medicines Agency. The drug received an orphan drug status in Europe in March 2012. Merck & Co. acquired the development and marketing rights to this experimental cancer drug from Endocyte in April 2012. The drug received orphan drug status in Europe in March 2012. Endocyte remains responsible for the development and commercialization of etarfolatide, a non-invasive companion imaging agent used to identify patients expressing the folate receptor that will likely respond to treatment with vintafolide. Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.
Merck ($MRK) and partner Endocyte ($ECYT) have stopped a late-stage study of the ovarian cancer-treating vintafolide on the advice of a data safety monitoring board, saying the much-hyped drug failed to move the needle on progression-free survival.
# Mechanism of action
Folate is required for cell division, and rapidly dividing cancer cells often express folate receptors in order to capture enough folate to support rapid cell growth. Elevated expression of the folate receptor occurs in many diseases, including other aggressively growing cancers and inflammatory disorders. Vintafolide binds to the folate receptor and is subsequently taken up by the cell through a natural internalization process called endocytosis. Once inside the cell, vintafolide’s linker releases the chemotherapy drug which kills the cell. | Vintafolide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
# Overview
Vintafolide is an investigational targeted cancer therapeutic currently under development by Endocyte and Merck & Co.[1] It is a small molecule drug conjugate consisting of a small molecule targeting the folate receptor, which is overexpressed on certain cancers, such as ovarian cancer, and a potent chemotherapy drug, vinblastine.[2] It is being developed with a companion imaging agent, etarfolatide, that identifies patients that express the folate receptor and thus would likely respond to the treatment with vintafolide.[3] A Phase 3 study evaluating vintafolide for the treatment of platinum-resistant ovarian cancer (PROCEED trial) and a Phase 2b study(TARGET trial) in non-small-cell lung carcinoma (NSCLC) are ongoing.[4] Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.[5]
A Marketing Authorization Application (MAA) filing for vintafolide and etarfolatide for the treatment of patients with folate receptor-positive platinum-resistant ovarian cancer in combination with doxorubicin, pegylated liposomal doxorubicin (PLD), has been accepted by the European Medicines Agency.[6] The drug received an orphan drug status in Europe in March 2012.[7] Merck & Co. acquired the development and marketing rights to this experimental cancer drug from Endocyte in April 2012.[8] The drug received orphan drug status in Europe in March 2012.[3] Endocyte remains responsible for the development and commercialization of etarfolatide, a non-invasive companion imaging agent used to identify patients expressing the folate receptor that will likely respond to treatment with vintafolide.[9] Vintafolide is designed to deliver the toxic vinblastine drug selectively to cells expressing the folate receptor using folate targeting.[10]
Merck ($MRK) and partner Endocyte ($ECYT) have stopped a late-stage study of the ovarian cancer-treating vintafolide on the advice of a data safety monitoring board, saying the much-hyped drug failed to move the needle on progression-free survival.[11]
# Mechanism of action
Folate is required for cell division, and rapidly dividing cancer cells often express folate receptors in order to capture enough folate to support rapid cell growth. Elevated expression of the folate receptor occurs in many diseases, including other aggressively growing cancers and inflammatory disorders.[12] Vintafolide binds to the folate receptor and is subsequently taken up by the cell through a natural internalization process called endocytosis. Once inside the cell, vintafolide’s linker releases the chemotherapy drug which kills the cell.[13] | https://www.wikidoc.org/index.php/Vintafolide | |
4bab87ceebfba142f8b68d6202296c32307d794d | wikidoc | Vinyl ether | Vinyl ether
# Overview
Vinyl ether, also known as divinyl ether, divinyl oxide, Vinethene (pharmaceutical trade name) and ethenoxyethene (IUPAC), is a clear, nearly colorless, volatile liquid which was briefly used as an inhalation anesthetic. It can be cyclopolymerized by itself and serves as a cross-linker in copolymerizations.
Much to the dismay of some pharmacologists, the synthesis and isolation of pure vinyl ether proved to be a difficult challenge for chemists; vinyl ether was suspected to be a nearly ideal anesthetic as its structure was the combination of an alkene and an ether. In practice, vinyl ether proved to have favorable properties that allowed its brief usage as an anesthetic; on the other hand, it left many unimpressed. Aggravated by the issue of potentially toxic degradation over long-term storage and possible hepatic toxicity, vinyl ether began to leave the operating theater. Today, vinyl ether is a relic in the field of anesthesiology; however, the analytical techniques used to study its pharmacology laid the groundwork for the testing of new anesthetic agents.
# History
## Synthetic
The first preparation of vinyl ether was reported in 1887 by Semmler. (Major, 1935) This chemist reported the production of vinyl ether from its sulfur substituted analogue, divinyl sulfide (obtained from the essential oil of Allium Ursinum L.), by reaction with silver oxide. Semmler's product which boiled at 39 °C was found to be sulfur free and molecular weight determinations were theoretically in accordance with vinyl ether.
In 1899, Knorr and Matthes attempted a synthesis of vinyl ether by exhaustive methylation of morpholine. (Major, 1935) They attained such a small quantity of product that no characterization was possible.
Cretcher et al. reported, in 1925, what would become the foundation for one industrial method used to produce vinyl ether. It was stated that the action of heated sodium hydroxide upon β,β`-dichlorodiethyl ether produced a liquid boiling at 39 °C (among other identified products). (Major, 1935) However, in a subtly modified process Hibbert et al. reported the isolation of a product boiling at 34-35 °C, "divinyl ether". Finally, in 1929, a patent issued to Merck & Co reported isolation of vinyl ether boiling ca. 28 °C. The currently accepted boiling point of vinyl ether is 28.3 °C; the Merck patent, therefore, was the first to report the isolation of a pure product.
## Anesthetic
Even before its isolation and characterization, the application of an unsaturated ether as an anesthetic interested some pharmacologists. One such pharmacologist, Chauncey Leake, was particularly captivated by the then theoretical vinyl ether. Leake predicted that vinyl ether would combine the properties of two anesthetic agents, ethyl ether, and ethylene. (Mazurek, 2007)
As an anesthetic ethylene has many favorable properties, although its very low potency often requires hypoxic conditions to achieve full anesthesia. Ethyl Ether on the other hand is a fairly potent anesthetic but falls short of ethylene in some respects. In comparison to ether, ethylene has a much lower occurrence of post operative nausea; additionally, ethylene has faster induction and recovery times than ether. (McIntosch, 1925)
Solely guided by predictions based upon structure, Leake perused the usage of vinyl ether as an inhalation anesthetic. (The Science News Letter, 1934) As vinyl ether was unknown in its pure form, Leake approached organic chemists at Berkeley asking them to synthesize this novel anesthetic. (Mazurek, 2007) Leake’s colleagues however, were unable to prepare vinyl ether; later though, Leake received help from two Princeton chemists, Randolph Major and W. T. Ruigh. Using samples received from Princeton, in 1930, Leake and fellow researcher Mei-Yu Chen published a brief study characterizing the anesthetic effects of vinyl ether upon mice. In the conclusion of this study, they cordially invited further research of this drug. (Mazurek, 2007)
This invitation was accepted; in 1933 Samuel Gelfan and Irving Bell of the University of Alberta published the first human trials of vinyl ether. They reported the experience of Gelfan himself as he was anesthetized with vinyl ether via the open drop technique. (The Science News Letter, 1934) Although, according to Leake, anesthesiologist Mary Botsford at the University of California was the first to clinically administer vinyl ether for a hysterectomy in early 1932. (Mazurek, 2007)
Thenceforth, vinyl ether was studied extensively at other institutions, though political climate at Berkeley hindered further study by Leake. Vinyl ether had some success but its usage was limited by aforementioned concerns of liver toxicity and degradation upon long term storage. (Mazurek, 2007)
# Properties
## Chemical
Vinyl Ether is a volatile, flammable liquid with a sweet, ethereal non-irritating odor (described to be similar to ethyl chloride). It is practically insoluble in water (.53g/100g water at 37 °C) but miscible with ethanol, ethyl ether, oils and other organic solvents.
Vinyl Ether is a rather unstable compound which with exposure to light or acid fumes decomposes to acetaldehyde and polymerizes into a glassy solid. Like many other ethers vinyl ether is also liable to form peroxides upon exposure to air and light. For these reasons vinyl ether is sold with inhibitors such as poly-phenols and amines to quell polymerization and peroxide formation. (Major, 1937) The anesthetic product was inhibited with .01% phenyl-α-napthylamine which gave it a faint violet fluorescence. (Finer, 1965)
Vinyl Ether rapidly decolorizes a solution of bromine in carbon tetrachloride; it is also rapidly oxidized by aqueous potassium permanganate; sulfuric acid reacts with vinyl ether producing a black tarry resin and some acetaldehyde. (Major, 1935)
## Anesthetic
In the United States, vinyl ether was sold under the trade name Vinethene. In addition to the normal inhibitors, vinyl ether intended for anesthetic use contained some ethanol (1.5-5%) to prevent frosting of the anesthetic mask. (Major, 1937) Despite inhibitors manufacturers warned that once opened vinyl ether should be used quickly. (Stumpf, 1935)
Vinyl ether has a rapid onset with little excitement upon induction. Induction causes little coughing however produces increased salivation. (Finer, 1965) During anesthesia vinyl ether can cause some patients to twitch. In rare cases this twitching can lead to convulsions; these convulsions are treatable. (Martin, 1941) Additionally, morphine-atropine pre-medication usually prevents this problem. (Finer, 1965) The recovery from vinyl ether is rapid with only rare cases of post operative nausea and vomiting, although headache after anesthesia sometimes occurs. (Finer, 1965)
Short operations pose little danger to the patient. Longer operations which use greater than 200ml of anesthetic can be dangerous due to hepatic and renal toxicity. In an attempt to circumvent the toxicity of vinyl ether while maintaining its favorable properties it was mixed 1:4 with ethyl ether producing ‘Vinethene Anesthetic Mixture’ (V.A.M.). V.A.M. shows smoother induction and recovery than ethyl ether alone yet is relatively non-toxic for longer procedures. (Finer, 1965) Though compared to ethyl ether V.A.M is less suitable for cases requiring deep anesthesia. (Martin, 1941)
Vinyl ether is a potent anesthetic giving it a large safety margin; the ratio of the anesthetic to lethal does for vinyl ether is 1 to 2.4 (ethyl ether: 1:1.5). (Anderson, 1937) However, this potency is hard to control with simplistic equipment. While anesthetic machines were numerous during the years of vinyl ether’s popularity, the simplistic ‘open drop technique’ also maintained its prevalence. Anesthetic machines of the time could suitably contain vinyl ether’s potency, however, via the open drop technique smooth anesthesia for long procedures was hard to sustain. (Martin, 1941) Further aggravating this problem, warm temperatures increase the volatility of vinyl ether making it even harder to regulate via the open drop technique. (Stumpf, 1935)
Overall, vinyl ether’s only strengths compared to ethyl ether are favorable induction and recovery. During anesthesia vinyl ether has no particularly wonderful properties and is harder to control than other agents. Therefore, vinyl ether was commonly used as a preliminary anesthetic before administration of diethyl ether. Additionally, vinyl ether was only used for short operations or analgesia, e.g. dentistry and obstetrics. Vinyl ether was used infrequently for long operations because of toxicity, cost, and superior alternatives.
Also, experiments were conducted with ethyl vinyl ether, a compound with one vinyl and one ethyl group. This substance produced results placing it between diethyl ether and divinyl ether both in terms of toxicity and speed of induction and recovery, producing promising results similar to V.A.M. (Grosskreutz, Davis 1956) Despite much simpler synthesis (vinylization of ethanol with acetylene) ethyl vinyl ether didn't enter widespread use in anasthetics, as superior halogenated ethers replaced it shortly after its first trials. | Vinyl ether
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Vinyl ether, also known as divinyl ether, divinyl oxide, Vinethene (pharmaceutical trade name) and ethenoxyethene (IUPAC), is a clear, nearly colorless, volatile liquid which was briefly used as an inhalation anesthetic. It can be cyclopolymerized by itself and serves as a cross-linker in copolymerizations.
Much to the dismay of some pharmacologists, the synthesis and isolation of pure vinyl ether proved to be a difficult challenge for chemists; vinyl ether was suspected to be a nearly ideal anesthetic as its structure was the combination of an alkene and an ether. In practice, vinyl ether proved to have favorable properties that allowed its brief usage as an anesthetic; on the other hand, it left many unimpressed. Aggravated by the issue of potentially toxic degradation over long-term storage and possible hepatic toxicity, vinyl ether began to leave the operating theater. Today, vinyl ether is a relic in the field of anesthesiology; however, the analytical techniques used to study its pharmacology laid the groundwork for the testing of new anesthetic agents.
# History
## Synthetic
The first preparation of vinyl ether was reported in 1887 by Semmler. (Major, 1935) This chemist reported the production of vinyl ether from its sulfur substituted analogue, divinyl sulfide (obtained from the essential oil of Allium Ursinum L.), by reaction with silver oxide. Semmler's product which boiled at 39 °C was found to be sulfur free and molecular weight determinations were theoretically in accordance with vinyl ether.
In 1899, Knorr and Matthes attempted a synthesis of vinyl ether by exhaustive methylation of morpholine. (Major, 1935) They attained such a small quantity of product that no characterization was possible.
Cretcher et al. reported, in 1925, what would become the foundation for one industrial method used to produce vinyl ether. It was stated that the action of heated sodium hydroxide upon β,β`-dichlorodiethyl ether produced a liquid boiling at 39 °C (among other identified products). (Major, 1935) However, in a subtly modified process Hibbert et al. reported the isolation of a product boiling at 34-35 °C, "divinyl ether". Finally, in 1929, a patent issued to Merck & Co reported isolation of vinyl ether boiling ca. 28 °C. The currently accepted boiling point of vinyl ether is 28.3 °C; the Merck patent, therefore, was the first to report the isolation of a pure product.
## Anesthetic
Even before its isolation and characterization, the application of an unsaturated ether as an anesthetic interested some pharmacologists. One such pharmacologist, Chauncey Leake, was particularly captivated by the then theoretical vinyl ether. Leake predicted that vinyl ether would combine the properties of two anesthetic agents, ethyl ether, and ethylene. (Mazurek, 2007)
As an anesthetic ethylene has many favorable properties, although its very low potency often requires hypoxic conditions to achieve full anesthesia. Ethyl Ether on the other hand is a fairly potent anesthetic but falls short of ethylene in some respects. In comparison to ether, ethylene has a much lower occurrence of post operative nausea; additionally, ethylene has faster induction and recovery times than ether. (McIntosch, 1925)
Solely guided by predictions based upon structure, Leake perused the usage of vinyl ether as an inhalation anesthetic. (The Science News Letter, 1934) As vinyl ether was unknown in its pure form, Leake approached organic chemists at Berkeley asking them to synthesize this novel anesthetic. (Mazurek, 2007) Leake’s colleagues however, were unable to prepare vinyl ether; later though, Leake received help from two Princeton chemists, Randolph Major and W. T. Ruigh. Using samples received from Princeton, in 1930, Leake and fellow researcher Mei-Yu Chen published a brief study characterizing the anesthetic effects of vinyl ether upon mice. In the conclusion of this study, they cordially invited further research of this drug. (Mazurek, 2007)
This invitation was accepted; in 1933 Samuel Gelfan and Irving Bell of the University of Alberta published the first human trials of vinyl ether. They reported the experience of Gelfan himself as he was anesthetized with vinyl ether via the open drop technique. (The Science News Letter, 1934) Although, according to Leake, anesthesiologist Mary Botsford at the University of California was the first to clinically administer vinyl ether for a hysterectomy in early 1932. (Mazurek, 2007)
Thenceforth, vinyl ether was studied extensively at other institutions, though political climate at Berkeley hindered further study by Leake. Vinyl ether had some success but its usage was limited by aforementioned concerns of liver toxicity and degradation upon long term storage. (Mazurek, 2007)
# Properties
## Chemical
Vinyl Ether is a volatile, flammable liquid with a sweet, ethereal non-irritating odor (described to be similar to ethyl chloride). It is practically insoluble in water (.53g/100g water at 37 °C) but miscible with ethanol, ethyl ether, oils and other organic solvents.
Vinyl Ether is a rather unstable compound which with exposure to light or acid fumes decomposes to acetaldehyde and polymerizes into a glassy solid. Like many other ethers vinyl ether is also liable to form peroxides upon exposure to air and light. For these reasons vinyl ether is sold with inhibitors such as poly-phenols and amines to quell polymerization and peroxide formation. (Major, 1937) The anesthetic product was inhibited with .01% phenyl-α-napthylamine which gave it a faint violet fluorescence. (Finer, 1965)
Vinyl Ether rapidly decolorizes a solution of bromine in carbon tetrachloride; it is also rapidly oxidized by aqueous potassium permanganate; sulfuric acid reacts with vinyl ether producing a black tarry resin and some acetaldehyde. (Major, 1935)
## Anesthetic
In the United States, vinyl ether was sold under the trade name Vinethene. In addition to the normal inhibitors, vinyl ether intended for anesthetic use contained some ethanol (1.5-5%) to prevent frosting of the anesthetic mask. (Major, 1937) Despite inhibitors manufacturers warned that once opened vinyl ether should be used quickly. (Stumpf, 1935)
Vinyl ether has a rapid onset with little excitement upon induction. Induction causes little coughing however produces increased salivation. (Finer, 1965) During anesthesia vinyl ether can cause some patients to twitch. In rare cases this twitching can lead to convulsions; these convulsions are treatable. (Martin, 1941) Additionally, morphine-atropine pre-medication usually prevents this problem. (Finer, 1965) The recovery from vinyl ether is rapid with only rare cases of post operative nausea and vomiting, although headache after anesthesia sometimes occurs. (Finer, 1965)
Short operations pose little danger to the patient. Longer operations which use greater than 200ml of anesthetic can be dangerous due to hepatic and renal toxicity. In an attempt to circumvent the toxicity of vinyl ether while maintaining its favorable properties it was mixed 1:4 with ethyl ether producing ‘Vinethene Anesthetic Mixture’ (V.A.M.). V.A.M. shows smoother induction and recovery than ethyl ether alone yet is relatively non-toxic for longer procedures. (Finer, 1965) Though compared to ethyl ether V.A.M is less suitable for cases requiring deep anesthesia. (Martin, 1941)
Vinyl ether is a potent anesthetic giving it a large safety margin; the ratio of the anesthetic to lethal does for vinyl ether is 1 to 2.4 (ethyl ether: 1:1.5). (Anderson, 1937) However, this potency is hard to control with simplistic equipment. While anesthetic machines were numerous during the years of vinyl ether’s popularity, the simplistic ‘open drop technique’ also maintained its prevalence. Anesthetic machines of the time could suitably contain vinyl ether’s potency, however, via the open drop technique smooth anesthesia for long procedures was hard to sustain. (Martin, 1941) Further aggravating this problem, warm temperatures increase the volatility of vinyl ether making it even harder to regulate via the open drop technique. (Stumpf, 1935)
Overall, vinyl ether’s only strengths compared to ethyl ether are favorable induction and recovery. During anesthesia vinyl ether has no particularly wonderful properties and is harder to control than other agents. Therefore, vinyl ether was commonly used as a preliminary anesthetic before administration of diethyl ether. Additionally, vinyl ether was only used for short operations or analgesia, e.g. dentistry and obstetrics. Vinyl ether was used infrequently for long operations because of toxicity, cost, and superior alternatives.
Also, experiments were conducted with ethyl vinyl ether, a compound with one vinyl and one ethyl group. This substance produced results placing it between diethyl ether and divinyl ether both in terms of toxicity and speed of induction and recovery, producing promising results similar to V.A.M. (Grosskreutz, Davis 1956) Despite much simpler synthesis (vinylization of ethanol with acetylene) ethyl vinyl ether didn't enter widespread use in anasthetics, as superior halogenated ethers replaced it shortly after its first trials. | https://www.wikidoc.org/index.php/Vinyl_ether | |
662639640ad18e3996c29548d99ec0d721ab7920 | wikidoc | Virotherapy | Virotherapy
Virotherapy is an experimental form of cancer treatment using biotechnology to convert viruses into cancer-fighting agents by reprogramming viruses to only attack cancerous cells while healthy cells remained undamaged. The human immunodeficiency virus (HIV), which causes AIDS, is a candidate for this and is currently under investigation. Usually the viruses used are Varicella Zoster Viruses (The Herpes simplex) and Adenoviruses(First isolated in adenoid tissue).
It uses viruses as treatment against various diseases, most commonly as a vector used to specifically target cells and DNA in particular. It is not a new idea - as early as the 1950's doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement: this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells.
In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumors. In 1956 some of the earliest human clinical trials with oncolytic viruses for the treatment of advanced-stage cervical cancer were started. However, for several years research in this field was delayed due to the inadequate technology available. Research has now started to move forward more quickly in finding ways to use viruses therapeutically.
In 2006 researchers from the Hebrew University succeeded in isolating a variant of the Newcastle disease Virus (NDV-HUJ), which usually affects birds, in order to specifically target cancer cells . The researchers tested the new virotherapy on Glioblastoma multiforme patients and achieved promising results for the first time. | Virotherapy
Virotherapy is an experimental form of cancer treatment using biotechnology to convert viruses into cancer-fighting agents by reprogramming viruses to only attack cancerous cells while healthy cells remained undamaged. The human immunodeficiency virus (HIV), which causes AIDS, is a candidate for this and is currently under investigation. Usually the viruses used are Varicella Zoster Viruses (The Herpes simplex) and Adenoviruses(First isolated in adenoid tissue).
It uses viruses as treatment against various diseases, most commonly as a vector used to specifically target cells and DNA in particular. It is not a new idea - as early as the 1950's doctors were noticing that cancer patients who suffered a non-related viral infection, or who had been vaccinated recently, showed signs of improvement: this has been largely attributed to the production of interferon and tumour necrosis factors in response to viral infection, but oncolytic viruses are being designed that selectively target and lyse only cancerous cells.
In the 1940s and 1950s, studies were conducted in animal models to evaluate the use of viruses in the treatment of tumors. In 1956 some of the earliest human clinical trials with oncolytic viruses for the treatment of advanced-stage cervical cancer were started. However, for several years research in this field was delayed due to the inadequate technology available. Research has now started to move forward more quickly in finding ways to use viruses therapeutically.
In 2006 researchers from the Hebrew University succeeded in isolating a variant of the Newcastle disease Virus (NDV-HUJ), which usually affects birds, in order to specifically target cancer cells [1]. The researchers tested the new virotherapy on Glioblastoma multiforme patients and achieved promising results for the first time. | https://www.wikidoc.org/index.php/Virotherapy | |
cd82be34a6e2bbeeed2475c2c158f248f96fc7e9 | wikidoc | Visual snow | Visual snow
Visual snow is a transitory or persisting visual symptom where people see snow or television-like static in parts or the whole of their visual fields, especially on dark backgrounds.
Visual snow is non-specific as regards etiology (cause of illness). Therefore, each subject with a leading complaint of visual snow needs a full diagnostic work-up including ophthalmic, neurological and psychiatric examinations as well as an MRI scan of the brain.
# Causes
Visual snow can occur in a variety of ophthalmic disorders that can be diagnosed by the presence of additional clinical signs and symptoms. Persisting visual snow can feature as a leading symptom of a migraine complication called persistent aura without infarction , first described under the designation prolonged migraine aura status. It is important to keep in mind that there exist many clinical sub-forms of migraine where headache may be absent and where the migraine aura may not take the typical form of the zigzagged fortification spectrum, but manifests with a large variety of focal neurological symptoms.
Another possible cause of visual snow is hallucinogen persisting perception disorder (HPPD) following use of LSD, MDMA, psilocybin or other hallucinogens. In HPPD, the symptom of visual snow has been described as aeropsia (literally "seeing the air"). It is noteworthy that HPPD can occur after a single dose of a hallucinogen and with a considerable latency between last drug intake and onset of persistent perception disorder, so taking a thorough life-time drug history is mandatory in the diagnostic-work up of visual snow.
Moreover, a variety of illnesses (e.g. Lyme disease, auto-immune disease) or nocious events (e.g. prolonged use of a VDU, dehydration, over-acidification) have been blamed by sufferers in self-help internet forums as causes of persisting visual snow, but none of these claims have been supported by evidence-based medicine. Some patients fail to find any apparent causative illness or event in their lives, instead saying the snow came out of nowhere or has been with them for their whole life.
# Related symptoms
In addition to visual snow, patients suffering from persistent perception disorder frequently have other types of visual disturbances such as starbursts, increased afterimages, floaters, trails, palinopsia and many others . Non-visual symptoms such as tinnitus or depersonalisation-derealisation are also frequently encountered. All of these additional symptoms have been described as manifestations of both migraine aura and HPPD, emphasizing the major importance of these two diagnoses for an explanation of the visual snow condition. Secondary psychiatric sequelae such as anxiety, panic attacks or depression may develop and necessitate appropriate treatment.
# What visual snow is not
According to the notion of hallucinatory form constants , visual snow can be conceived as a variety of visual hallucinations of random form dimension. As such, the phenomenon should not be confused with normal entoptic phenomena such as Haidinger's brush, which almost never have sufficient intensity to gain clinical significance as a source of suffering or functional impairment.
# Treatments
There currently is no established treatment for visual snow. In HPPD, clonazepam has been recommended as medication of first choice in patients seeking medical help . Furthermore, drug abstinence is of major therapeutic importance in HPPD. In persistent aura without infarction, the evidence so far suggests that acetazolamide may be the premier drug for patients with the repetitive form of aura status and that valproate , lamotrigine , or topiramate should be first choices for patients with the continuous form. When these oral drugs are ineffective, an intravenous injection or injections of furosemide should be tried . However, with very little scientific research on the condition taking place, for the time being the effectiveness of such treatments remains based solely on anecdotal evidence. Beyond pharmacological approaches, appropriate counselling and cognitive behavioral interventions that focus on coping with the condition may be of huge importance. | Visual snow
Visual snow is a transitory or persisting visual symptom where people see snow or television-like static in parts or the whole of their visual fields, especially on dark backgrounds.
Visual snow is non-specific as regards etiology (cause of illness). Therefore, each subject with a leading complaint of visual snow needs a full diagnostic work-up including ophthalmic, neurological and psychiatric examinations as well as an MRI scan of the brain.
# Causes
Visual snow can occur in a variety of ophthalmic disorders that can be diagnosed by the presence of additional clinical signs and symptoms. Persisting visual snow can feature as a leading symptom of a migraine complication called persistent aura without infarction [1], first described [2] under the designation prolonged migraine aura status. It is important to keep in mind that there exist many clinical sub-forms of migraine where headache may be absent and where the migraine aura may not take the typical form of the zigzagged fortification spectrum, but manifests with a large variety of focal neurological symptoms.
Another possible cause of visual snow is hallucinogen persisting perception disorder (HPPD) following use of LSD, MDMA, psilocybin or other hallucinogens. In HPPD, the symptom of visual snow has been described [3] as aeropsia (literally "seeing the air"). It is noteworthy that HPPD can occur after a single dose of a hallucinogen and with a considerable latency between last drug intake and onset of persistent perception disorder, so taking a thorough life-time drug history is mandatory in the diagnostic-work up of visual snow.
Moreover, a variety of illnesses (e.g. Lyme disease, auto-immune disease) or nocious events (e.g. prolonged use of a VDU, dehydration, over-acidification) have been blamed by sufferers in self-help internet forums as causes of persisting visual snow, but none of these claims have been supported by evidence-based medicine. Some patients fail to find any apparent causative illness or event in their lives, instead saying the snow came out of nowhere or has been with them for their whole life.
# Related symptoms
In addition to visual snow, patients suffering from persistent perception disorder frequently have other types of visual disturbances such as starbursts, increased afterimages, floaters, trails, palinopsia and many others [4]. Non-visual symptoms such as tinnitus or depersonalisation-derealisation are also frequently encountered. All of these additional symptoms have been described as manifestations of both migraine aura and HPPD, emphasizing the major importance of these two diagnoses for an explanation of the visual snow condition. Secondary psychiatric sequelae such as anxiety, panic attacks or depression may develop and necessitate appropriate treatment.
# What visual snow is not
According to the notion of hallucinatory form constants [5][6], visual snow can be conceived as a variety of visual hallucinations of random form dimension. As such, the phenomenon should not be confused with normal entoptic phenomena such as Haidinger's brush, which almost never have sufficient intensity to gain clinical significance as a source of suffering or functional impairment.
# Treatments
There currently is no established treatment for visual snow. In HPPD, clonazepam has been recommended as medication of first choice in patients seeking medical help [7]. Furthermore, drug abstinence is of major therapeutic importance in HPPD. In persistent aura without infarction, the evidence so far suggests that acetazolamide may be the premier drug for patients with the repetitive form of aura status [8] and that valproate [9], lamotrigine [10], or topiramate [11] should be first choices for patients with the continuous form. When these oral drugs are ineffective, an intravenous injection or injections of furosemide should be tried [12]. However, with very little scientific research on the condition taking place, for the time being the effectiveness of such treatments remains based solely on anecdotal evidence. Beyond pharmacological approaches, appropriate counselling and cognitive behavioral interventions that focus on coping with the condition may be of huge importance. | https://www.wikidoc.org/index.php/Visual_snow | |
40cb28dcfe76326d42368c3d8e37eaafef1d901c | wikidoc | Vital signs | Vital signs
Vital signs are measures of various physiological statistics often taken by health professionals in order to assess the most basic body functions. Vital signs are an essential part of a case presentation.
# Primary four
There are four vital signs which are standard in most medical settings:
- Body Temperature
- Pulse rate (or heart rate)
- Blood pressure
- Respiratory rate
The equipment needed is a thermometer, a sphygmomanometer, and a watch with a second hand.
Though a pulse can often be taken by hand, a stethoscope may be required for a patient with a very weak pulse.
# Additional signs
## Fifth sign
The phrase "fifth vital sign" usually refers to pain, as perceived by the patient on a Pain scale of 0-10. For example, the Veterans Administration made this their policy in 1999. However, some doctors have noted that pain is actually a subjective symptom, not an objective sign, and therefore object to this classification.
Other sources include pulse oximetry as their fifth sign.
Some sources consider pupil size, equality, and reactivity to light to be a vital sign as well.
## Sixth sign
There is no standard "sixth vital sign", and the use is much more informal and discipline-dependent than with the above, but some proposals (excluding the fifth sign candidates above) include:
- Urinary continence
- End-tidal CO2
- Emotional distress
- Spirometry
- Glucose
- Functional Status
- Oxygen saturation level
- Intracranial pressure
- Skin signs (color)
# Variations by age
Children and infants have respiratory and heart rates that are faster than those of adults as shown in the following table: | Vital signs
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Vital signs are measures of various physiological statistics often taken by health professionals in order to assess the most basic body functions. Vital signs are an essential part of a case presentation.
# Primary four
There are four vital signs which are standard in most medical settings:
- Body Temperature
- Pulse rate (or heart rate)
- Blood pressure
- Respiratory rate
The equipment needed is a thermometer, a sphygmomanometer, and a watch with a second hand.
Though a pulse can often be taken by hand, a stethoscope may be required for a patient with a very weak pulse.
# Additional signs
## Fifth sign
The phrase "fifth vital sign" usually refers to pain, as perceived by the patient on a Pain scale of 0-10. For example, the Veterans Administration made this their policy in 1999. However, some doctors have noted that pain is actually a subjective symptom, not an objective sign, and therefore object to this classification.[1]
Other sources include pulse oximetry as their fifth sign.[2][3][4]
Some sources consider pupil size, equality, and reactivity to light to be a vital sign as well.[5]
## Sixth sign
There is no standard "sixth vital sign", and the use is much more informal and discipline-dependent than with the above, but some proposals (excluding the fifth sign candidates above) include:
- Urinary continence[6]
- End-tidal CO2[7]
- Emotional distress[8]
- Spirometry[9]
- Glucose[10]
- Functional Status[11]
- Oxygen saturation level
- Intracranial pressure
- Skin signs (color)
# Variations by age
Children and infants have respiratory and heart rates that are faster than those of adults as shown in the following table: | https://www.wikidoc.org/index.php/Vital | |
80e463efd5ecc36fd45a2e00d0f433c161d1a7b8 | wikidoc | Vitronectin | Vitronectin
Vitronectin (VTN or VN) is a glycoprotein of the hemopexin family which is abundantly found in serum, the extracellular matrix and bone. In humans it is encoded by the VTN gene.
Vitronectin binds to integrin alpha-V beta-3 and thus promotes cell adhesion and spreading. It also inhibits the membrane-damaging effect of the terminal cytolytic complement pathway and binds to several serpins (serine protease inhibitors). It is a secreted protein and exists in either a single chain form or a clipped, two chain form held together by a disulfide bond. Vitronectin has been speculated to be involved in hemostasis and tumor malignancy.
# Structure
Vitronectin is a 75 kDa glycoprotein, consisting of 459 amino acid residues. About one-third of the protein's molecular mass is composed of carbohydrates. On occasion, the protein is cleaved after arginine 379, to produce two-chain vitronectin, where the two parts are linked by a disulfide bond. No high-resolution structure has been determined experimentally yet,
except for the N-terminal domain.
The protein consists of three domains:
- The N-terminal Somatomedin B domain (1-39)
- A central domains with hemopexin homology (131-342)
- A C-terminal domain (residues 347-459) also with hemopexin homology.
Several structures has been reported for the Somatomedin B domain. The protein was initially crystallized in complex with one of its physiological binding partners: the Plasminogen activator inhibitor-1 (PAI-1) and the structure solved for this complex. Subsequently two groups reported NMR structures of the domain.
The somatomedin B domain is a close-knit disulfide knot, with 4 disulfide bonds within 35 residues. Different disulfide configurations had been reported for this domain but this ambiguity has been resolved by the crystal structure.
Homology models have been built for the central and C-terminal domains.
# Function
The somatomedin B domain of vitronectin binds to plasminogen activator inhibitor-1 (PAI-1), and stabilizes it. Thus vitronectin serves to regulate proteolysis initiated by plasminogen activation. In addition, vitronectin is a component of platelets and is, thus, involved in hemostasis. Vitronectin contains an RGD (45-47) sequence, which is a binding site for membrane-bound integrins, e.g., the vitronectin receptor, which serve to anchor cells to the extracellular matrix. The Somatomedin B domain interacts with the urokinase receptor, and this interaction has been implicated in cell migration and signal transduction. High plasma levels of both PAI-1 and the urokinase receptor have been shown to correlate with a negative prognosis for cancer patients. Cell adhesion and migration are directly involved in cancer metastasis, which provides a probable mechanistic explanation for this observation. | Vitronectin
Vitronectin (VTN or VN) is a glycoprotein of the hemopexin family which is abundantly found in serum, the extracellular matrix and bone.[1] In humans it is encoded by the VTN gene.[2][3]
Vitronectin binds to integrin alpha-V beta-3 and thus promotes cell adhesion and spreading. It also inhibits the membrane-damaging effect of the terminal cytolytic complement pathway and binds to several serpins (serine protease inhibitors). It is a secreted protein and exists in either a single chain form or a clipped, two chain form held together by a disulfide bond.[2] Vitronectin has been speculated to be involved in hemostasis[4] and tumor malignancy.[5][6]
# Structure
Vitronectin is a 75 kDa glycoprotein, consisting of 459 amino acid residues. About one-third of the protein's molecular mass is composed of carbohydrates. On occasion, the protein is cleaved after arginine 379, to produce two-chain vitronectin, where the two parts are linked by a disulfide bond. No high-resolution structure has been determined experimentally yet,
except for the N-terminal domain.
The protein consists of three domains:
- The N-terminal Somatomedin B domain (1-39)
- A central domains with hemopexin homology (131-342)
- A C-terminal domain (residues 347-459) also with hemopexin homology.
Several structures has been reported for the Somatomedin B domain. The protein was initially crystallized in complex with one of its physiological binding partners: the Plasminogen activator inhibitor-1 (PAI-1) and the structure solved for this complex.[7] Subsequently two groups reported NMR structures of the domain.[8][9]
The somatomedin B domain is a close-knit disulfide knot, with 4 disulfide bonds within 35 residues. Different disulfide configurations had been reported for this domain[10][11][12] but this ambiguity has been resolved by the crystal structure.[12]
Homology models have been built for the central and C-terminal domains.[12]
# Function
The somatomedin B domain of vitronectin binds to plasminogen activator inhibitor-1 (PAI-1), and stabilizes it.[7] Thus vitronectin serves to regulate proteolysis initiated by plasminogen activation. In addition, vitronectin is a component of platelets and is, thus, involved in hemostasis. Vitronectin contains an RGD (45-47) sequence, which is a binding site for membrane-bound integrins, e.g., the vitronectin receptor, which serve to anchor cells to the extracellular matrix. The Somatomedin B domain interacts with the urokinase receptor, and this interaction has been implicated in cell migration and signal transduction. High plasma levels of both PAI-1 and the urokinase receptor have been shown to correlate with a negative prognosis for cancer patients. Cell adhesion and migration are directly involved in cancer metastasis, which provides a probable mechanistic explanation for this observation. | https://www.wikidoc.org/index.php/Vitronectin | |
0ceb1cc5386c4aee0379a2e4d5ddcd327d3586d0 | wikidoc | Vivisection | Vivisection
Etymologically, vivisection refers to the dissection of, or any cutting or surgery upon, a living organism. More broadly, it is sometimes used to describe any invasive experiment upon living animals. For some, the word has a pejorative connotation, implying torture and suffering.
- For vivisection on human beings, see Human experimentation.
# Sources
- ↑ "Vivisection", Encyclopaedia Britannica, 2007. Also see Croce, Pietro. Vivisection or Science? An Investigation into Testing Drugs and Safeguarding Health. Zed Books, 1999, and "FAQs: Vivisection", British Union for the Abolition of Vivisection.
- ↑ Carbone, Larry. What Animals Want: Expertise and Advocacy in Laboratory Animal Welfare. Oxford University Press, 2004, p. 22. | Vivisection
Etymologically, vivisection refers to the dissection of, or any cutting or surgery upon, a living organism. More broadly, it is sometimes used to describe any invasive experiment upon living animals.[1] For some, the word has a pejorative connotation, implying torture and suffering. [2]
- For vivisection on human beings, see Human experimentation.
# Sources
- ↑ "Vivisection", Encyclopaedia Britannica, 2007. Also see Croce, Pietro. Vivisection or Science? An Investigation into Testing Drugs and Safeguarding Health. Zed Books, 1999, and "FAQs: Vivisection", British Union for the Abolition of Vivisection.
- ↑ Carbone, Larry. What Animals Want: Expertise and Advocacy in Laboratory Animal Welfare. Oxford University Press, 2004, p. 22.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Vivisection | |
f1bca03bf1075a36f28d61dcc78f41173661f486 | wikidoc | Vocal range | Vocal range
Human voices may be classified according to their vocal range — the highest and lowest pitches that they can produce.
# Vocal range defined
The broadest definition of vocal range, given above, is simply the span from the highest to the lowest note a particular voice can produce. This broad definition, however, is quite often not the one meant when someone speaks of "vocal range." This is because some of the notes a voice can produce may not be considered "musically useful" for a particular purpose. For example, when speaking of the vocal range of a male opera singer, one usually excludes falsetto pitches, which are not used in most opera. A male doo-wop singer, on the other hand, might quite regularly deploy his falsetto pitches in performance and thus include them in determining his range.
For this reason, it is important to clearly define what is meant when discussing a vocal range. For example, one might say of a man that he has a two and one-half octave range in full voice and an additional one half octave in falsetto. Similarly, when discussing the range of a woman one might say that she has a "useful" two octave range with an additional major third on the bottom that is only audible with amplification. Unfortunately, there is no standardization in this nomenclature outside of classical unamplified singing.
# Vocal range in classical music
Vocal range is generally very important in classical music. In opera and solo classical music, two considerations are paramount in determining vocal range: consistency of timbre across the vocal range, and ability to project the pitches (that is, to be heard clearly over an orchestra without amplification). Of course, if any pitch cannot be properly projected, it is not considered part of the range. See voice type.
Choral music is somewhat less stringent than opera. In contrast to opera, the large number of voices that can be deployed in each group make it somewhat less important that each individual voice be flawlessly produced and completely audible. Thus, for example, choirs can often deploy notes that are lower than those that might be deployed in an operatic performance - no single member of the choir might be able to project such a low note individually, but taken together the note might be quite audible.
In much choral music the vocal ranges are often divided not into the three parts per sex as they are in operatic solo music but into only two parts per gender - Soprano, Alto, Tenor, Bass - or into four parts per sex - Soprano I, Soprano II, Alto I, Alto II, Tenor I, Tenor II, Bass I (or baritone), Bass II. For example see the Mass in B Minor. There is therefore some ambiguity in mapping the solo baritone voice defined in the three way solo system to the four way choral system. Many high baritone soloists like Sherrill Milnes might have sung Second Tenor in a chorus, (usually not a preferred compromise) whereas other baritones such as Bryn Terfel might have sung First Bass. They would have had to choose one or the other as any baritone part is labeled in that manner.
# Classification of vocal range
Basic Operatic Ranges:
- Soprano: C4 - C6
- Mezzo-Soprano: A3 - A5
- Contralto: E3 - E5
- Tenor: C3 - C5
- Baritone: G2 - G4
- Bass: E2 - E4
Note: Depending upon the conductor's vocal exercises & observations, an individual may possess an extended range which may allow a shifting of choral sections.
Basic Choral ranges:
- Soprano: C4 - A5
- Mezzo-Soprano: A3 - F5
- Contralto: F3 - D5
- Tenor: B2 - G4
- Baritone: G2 - E4
- Bass/Basso: E2 - C4
A soprano who can sing higher than CTemplate:Music6 is known as a sopranino and a Bass who can sing G1 or lower is known as a sub-bass singer or a basso profondo. However, many people will still call sopraninos sopranos and basso profondos basses/bassos.
Male falsetto and female flageolet register can extend the vocal range of a singer higher.
Males who possess high ranges or can project falsetto, are referred to as countertenors and possess ranges equivalent to those of the female ranges, alto, mezzo-soprano and soprano (a male soprano is specifically referred to as sopranist). Contraltos have been known to sing Tenor (although this is strongly discouraged, especially among younger contraltos), and occasionally men will sing in the upper three ranges.
In addition to these general classifications, additional subdivisions are very commonly deployed in opera and other classical music for solo voice. There are a number of such detailed classification schemes, some of which are historical or country-specific. See voice type.
## Induced vocal range
Where the above are largely achieved through practice and natural aptitude, adult vocal ranges can be obtained by means of physiological modification. The most notable example of this would be castrato singers, although modern examples include the lowering of the voice through Tobacco smoking.
# Vocal range in terms of frequency
In terms of frequency, human voices are roughly in the range of 80 Hz to 1100 Hz (that is, E2 to C6) for normal male and female voices together. The world records for high and low pitch extend well outside of this range, and can extend outside the range of human hearing.
# World records and extremes of vocal range
As noted above, claims of exceptionally wide vocal ranges are not uncommon among some singers. The biggest claim came from Charles Kellogg, who claimed to have a vocal range of 12.5 octaves. Kellogg could accurately imitate birdcalls, which sometimes went up into the ultrasonic range, according to Kellogg as high as 14,000 Hz (14 080Hz is A9). Some recordings of Kellogg's birdcalls still exist. However, Kellogg's claims are very hard to verify.
In 2006 the Guinness Book of Records published several categories relating to extremes of "Human vocal range." It stated the following:
Females
- Greatest range: Eight octaves G2-G10, Georgia Brown, Brazil Watch Here (example of E7)
- Highest vocal note: G10 (25087Hz), Georgia Brown, Brazil
- Guinness lists the highest demanded note in the classical repertoire as G6 in 'Popoli di Tessaglia,' a concert aria by W. A. Mozart. However, this is not a standard repertory piece. The highest note in the standard repertoire is F6 in Mozart's aria "Der Hölle Rache kocht in meinem Herzen" Watch Clip" (sometimes called "The Queen of the Night's aria," though this character actually has two arias) from the opera Die Zauberflöte. It calls for four F6's, which is often cited as the highest note in classical vocal music (she sings an additional F6 during the first Act aria, "O Zittre nicht"). Several little-known works call for pitches higher than G6. For example, the soprano Mado Robin, who was known for her exceptionally high voice, sang a number of compositions created especially to exploit her highest notes, reaching C7 according to the Concise Oxford Dictionary of Opera (edited by Harold Rosenthal)
Males
- Greatest range: Six octaves, Tim Storms, USA Watch Clip
- Highest vocal note: CTemplate:Music8 Adam Lopez, Australia Watch Clip
- Lowest vocal note: B-2 (minus 2, two octaves below the grand staff)(8 Hz), Tim Storms, USA
- Guinness lists the lowest demanded note in the classical repertoire as a "Low D" (two Ds below Middle C) in Osmin's aria in Mozart's Die Entführung aus dem Serail. Although Osmin's note is the lowest demanded and commonly performed in the operatic repertoire, Mahler's second symphony contains an optional BTemplate:Music1 in the choral section at the end of the piece: basses who cannot reach it are requested to remain silent rather than sing a BTemplate:Music2. Leonard Bernstein's Candide has an optional low B (a minor third below the low D) in a bass aria of its opera house version. Some choral works and songs also call for notes lower than the low D. For example, Pavel Chesnokov's "Do not deny me in my old age" features a basso profundo soloist, sometimes reaching as low as G1, depending on the arrangement. | Vocal range
Human voices may be classified according to their vocal range — the highest and lowest pitches that they can produce.
Template:Vocal range
# Vocal range defined
The broadest definition of vocal range, given above, is simply the span from the highest to the lowest note a particular voice can produce. This broad definition, however, is quite often not the one meant when someone speaks of "vocal range." This is because some of the notes a voice can produce may not be considered "musically useful" for a particular purpose. For example, when speaking of the vocal range of a male opera singer, one usually excludes falsetto pitches, which are not used in most opera. A male doo-wop singer, on the other hand, might quite regularly deploy his falsetto pitches in performance and thus include them in determining his range.
For this reason, it is important to clearly define what is meant when discussing a vocal range. For example, one might say of a man that he has a two and one-half octave range in full voice and an additional one half octave in falsetto. Similarly, when discussing the range of a woman one might say that she has a "useful" two octave range with an additional major third on the bottom that is only audible with amplification. Unfortunately, there is no standardization in this nomenclature outside of classical unamplified singing.
# Vocal range in classical music
Vocal range is generally very important in classical music. In opera and solo classical music, two considerations are paramount in determining vocal range: consistency of timbre across the vocal range, and ability to project the pitches (that is, to be heard clearly over an orchestra without amplification). Of course, if any pitch cannot be properly projected, it is not considered part of the range. See voice type.
Choral music is somewhat less stringent than opera. In contrast to opera, the large number of voices that can be deployed in each group make it somewhat less important that each individual voice be flawlessly produced and completely audible. Thus, for example, choirs can often deploy notes that are lower than those that might be deployed in an operatic performance - no single member of the choir might be able to project such a low note individually, but taken together the note might be quite audible.
In much choral music the vocal ranges are often divided not into the three parts per sex as they are in operatic solo music but into only two parts per gender - Soprano, Alto, Tenor, Bass - or into four parts per sex - Soprano I, Soprano II, Alto I, Alto II, Tenor I, Tenor II, Bass I (or baritone), Bass II. For example see the Mass in B Minor. There is therefore some ambiguity in mapping the solo baritone voice defined in the three way solo system to the four way choral system. Many high baritone soloists like Sherrill Milnes might have sung Second Tenor in a chorus, (usually not a preferred compromise) whereas other baritones such as Bryn Terfel might have sung First Bass. They would have had to choose one or the other as any baritone part is labeled in that manner.
# Classification of vocal range
Template:Vocal ranges visual
Basic Operatic Ranges:
- Soprano: C4 - C6
- Mezzo-Soprano: A3 - A5
- Contralto: E3 - E5
- Tenor: C3 - C5
- Baritone: G2 - G4
- Bass: E2 - E4
Note: Depending upon the conductor's vocal exercises & observations, an individual may possess an extended range which may allow a shifting of choral sections.
Basic Choral ranges:[1]
- Soprano: C4 - A5
- Mezzo-Soprano: A3 - F5
- Contralto: F3 - D5
- Tenor: B2 - G4
- Baritone: G2 - E4
- Bass/Basso: E2 - C4
A soprano who can sing higher than CTemplate:Music6 is known as a sopranino and a Bass who can sing G1 or lower is known as a sub-bass singer or a basso profondo. However, many people will still call sopraninos sopranos and basso profondos basses/bassos.
Male falsetto and female flageolet register can extend the vocal range of a singer higher.
Males who possess high ranges or can project falsetto, are referred to as countertenors and possess ranges equivalent to those of the female ranges, alto, mezzo-soprano and soprano (a male soprano is specifically referred to as sopranist). Contraltos have been known to sing Tenor (although this is strongly discouraged, especially among younger contraltos), and occasionally men will sing in the upper three ranges.
In addition to these general classifications, additional subdivisions are very commonly deployed in opera and other classical music for solo voice. There are a number of such detailed classification schemes, some of which are historical or country-specific. See voice type.
## Induced vocal range
Where the above are largely achieved through practice and natural aptitude, adult vocal ranges can be obtained by means of physiological modification. The most notable example of this would be castrato singers, although modern examples include the lowering of the voice through Tobacco smoking.
# Vocal range in terms of frequency
In terms of frequency, human voices are roughly in the range of 80 Hz to 1100 Hz (that is, E2 to C6) for normal male and female voices together. The world records for high and low pitch extend well outside of this range, and can extend outside the range of human hearing.
# World records and extremes of vocal range
As noted above, claims of exceptionally wide vocal ranges are not uncommon among some singers. The biggest claim came from Charles Kellogg, who claimed to have a vocal range of 12.5 octaves. Kellogg could accurately imitate birdcalls, which sometimes went up into the ultrasonic range, according to Kellogg as high as 14,000 Hz (14 080Hz is A9). Some recordings of Kellogg's birdcalls still exist. However, Kellogg's claims are very hard to verify. [2]
In 2006 the Guinness Book of Records published several categories relating to extremes of "Human vocal range." It stated the following:
Females
- Greatest range: Eight octaves G2-G10, Georgia Brown, Brazil Watch Here (example of E7)
- Highest vocal note: G10 (25087Hz), Georgia Brown, Brazil
- Guinness lists the highest demanded note in the classical repertoire as G6 in 'Popoli di Tessaglia,' a concert aria by W. A. Mozart. However, this is not a standard repertory piece. The highest note in the standard repertoire is F6 in Mozart's aria "Der Hölle Rache kocht in meinem Herzen" Watch Clip" (sometimes called "The Queen of the Night's aria," though this character actually has two arias) from the opera Die Zauberflöte. It calls for four F6's, which is often cited as the highest note in classical vocal music (she sings an additional F6 during the first Act aria, "O Zittre nicht"). Several little-known works call for pitches higher than G6. For example, the soprano Mado Robin, who was known for her exceptionally high voice, sang a number of compositions created especially to exploit her highest notes, reaching C7 according to the Concise Oxford Dictionary of Opera (edited by Harold Rosenthal)
Males
- Greatest range: Six octaves, Tim Storms, USA Watch Clip
- Highest vocal note: CTemplate:Music8 Adam Lopez, Australia Watch Clip
- Lowest vocal note: B-2 (minus 2, two octaves below the grand staff)(8 Hz), Tim Storms, USA
- Guinness lists the lowest demanded note in the classical repertoire as a "Low D" (two Ds below Middle C) in Osmin's aria in Mozart's Die Entführung aus dem Serail. Although Osmin's note is the lowest demanded and commonly performed in the operatic repertoire, Mahler's second symphony contains an optional BTemplate:Music1 in the choral section at the end of the piece: basses who cannot reach it are requested to remain silent rather than sing a BTemplate:Music2. Leonard Bernstein's Candide has an optional low B (a minor third below the low D) in a bass aria of its opera house version. Some choral works and songs also call for notes lower than the low D. For example, Pavel Chesnokov's "Do not deny me in my old age" features a basso profundo soloist, sometimes reaching as low as G1, depending on the arrangement. | https://www.wikidoc.org/index.php/Vocal_range | |
fe96703a06e63b5c1300af5e0df9600bbcb63d03 | wikidoc | Volvariella | Volvariella
Volvariella is a genus of mushrooms with pink gills and spore prints. They lack a ring, and have an Amanita-like volva at the stem base. Some species of Amanita look similar, but Amanita has white spores and often have a ring. Since the gills of young Volvariella are white at first, they are more easily mistaken for Amanita.
Many sources list Volvariella as a member of the Pluteaceae family, but recent DNA studies have revealed that Pluteus and Volvareilla evolved separately and have very different DNA. These studies show that Volvariella is very closely related to "schizophylloid" mushrooms like Schizophyllum commune.
Some species of Volvariella are popular edibles in Europe, accounting for 16% of total production of cultivated mushrooms in the world.
Volvariella volvacea, well known as the "paddy straw mushroom," is cultured in rice straw in the Philippines and Southeast Asia. This species also favours wood chip piles. Unfortunately, it is easy to mistake the death cap mushroom (Amanita phalloides), as well as some other Amanita species, for this edible species due to similarities in appearance. This mistake is the leading cause of lethal mushroom poisoning in the United States. Volvariella and Amanita cannot be distinguished in the early "button stage", that, for many, is considered the best stage to collect Volvariella for consumption. Like Amanita, the paddy straw mushroom has a volva, or universal veil, so called because it is a membrane that encapsulates the entire mushroom when it is young. This structure breaks apart as the mushroom expands, leaving parts that can be found at the base of the stalk as a cup-like structure.
# List of Species
- File:Unknown toxicity icon.pngVolvariella bombycina
- File:Edible toxicity icon.pngVolvariella gloiocephala
- File:Unknown toxicity icon.pngVolvariella hypopithys
- File:Unknown toxicity icon.pngVolvariella jamaicensis
- File:Unknown toxicity icon.pngVolvariella lepiotospora
- File:Unknown toxicity icon.pngVolvariella peckii
- File:Edible toxicity icon.pngVolvariella speciosa
- File:Unknown toxicity icon.pngVolvariella surrecta
- File:Choice toxicity icon.pngVolvariella volvacea | Volvariella
Volvariella is a genus of mushrooms with pink gills and spore prints. They lack a ring, and have an Amanita-like volva at the stem base. Some species of Amanita look similar, but Amanita has white spores and often have a ring. Since the gills of young Volvariella are white at first, they are more easily mistaken for Amanita.
Many sources list Volvariella as a member of the Pluteaceae family, but recent DNA studies have revealed that Pluteus and Volvareilla evolved separately and have very different DNA. These studies show that Volvariella is very closely related to "schizophylloid" mushrooms like Schizophyllum commune. [1]
Some species of Volvariella are popular edibles in Europe, accounting for 16% of total production of cultivated mushrooms in the world.
Volvariella volvacea, well known as the "paddy straw mushroom," is cultured in rice straw in the Philippines and Southeast Asia. This species also favours wood chip piles. Unfortunately, it is easy to mistake the death cap mushroom (Amanita phalloides), as well as some other Amanita species, for this edible species due to similarities in appearance. This mistake is the leading cause of lethal mushroom poisoning in the United States. Volvariella and Amanita cannot be distinguished in the early "button stage", that, for many, is considered the best stage to collect Volvariella for consumption. Like Amanita, the paddy straw mushroom has a volva, or universal veil, so called because it is a membrane that encapsulates the entire mushroom when it is young. This structure breaks apart as the mushroom expands, leaving parts that can be found at the base of the stalk as a cup-like structure.
# List of Species
- File:Unknown toxicity icon.pngVolvariella bombycina
- File:Edible toxicity icon.pngVolvariella gloiocephala
- File:Unknown toxicity icon.pngVolvariella hypopithys
- File:Unknown toxicity icon.pngVolvariella jamaicensis
- File:Unknown toxicity icon.pngVolvariella lepiotospora
- File:Unknown toxicity icon.pngVolvariella peckii
- File:Edible toxicity icon.pngVolvariella speciosa
- File:Unknown toxicity icon.pngVolvariella surrecta
- File:Choice toxicity icon.pngVolvariella volvacea | https://www.wikidoc.org/index.php/Volvariella | |
7c27c6bd06d6450106e820aa16778c8c50a95b64 | wikidoc | WASL (gene) | WASL (gene)
Neural Wiskott-Aldrich syndrome protein is a protein that in humans is encoded by the WASL gene.
The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. The WASL gene product is a homolog of WAS protein, however, unlike the latter, it is ubiquitously expressed and shows highest expression in neural tissues. It has been shown to bind Cdc42 directly, and induce formation of long actin microspikes.
According to one study, mouse DAB1 regulates actin cytoskeleton through N-WASP.
Diseases associated with WASL include Wiskottt-Aldrich Syndrome and Vaccinia.
# Interactions
WASL (gene) has been shown to interact with:
- CDC42,
- Cortactin
- NCK1,
- Profilin 1, and
- RHOQ. | WASL (gene)
Neural Wiskott-Aldrich syndrome protein is a protein that in humans is encoded by the WASL gene.[1][2][3]
The Wiskott-Aldrich syndrome (WAS) family of proteins share similar domain structure, and are involved in transduction of signals from receptors on the cell surface to the actin cytoskeleton. The presence of a number of different motifs suggests that they are regulated by a number of different stimuli, and interact with multiple proteins. Recent studies have demonstrated that these proteins, directly or indirectly, associate with the small GTPase, Cdc42, known to regulate formation of actin filaments, and the cytoskeletal organizing complex, Arp2/3. The WASL gene product is a homolog of WAS protein, however, unlike the latter, it is ubiquitously expressed and shows highest expression in neural tissues. It has been shown to bind Cdc42 directly, and induce formation of long actin microspikes.[3]
According to one study, mouse DAB1 regulates actin cytoskeleton through N-WASP.[4]
Diseases associated with WASL include Wiskottt-Aldrich Syndrome and Vaccinia.[5]
# Interactions
WASL (gene) has been shown to interact with:
- CDC42,[1][6]
- Cortactin[7]
- NCK1,[8]
- Profilin 1,[9][10] and
- RHOQ.[11] | https://www.wikidoc.org/index.php/WASL_(gene) | |
a31561335ef14b2dbe1d1e0e4f33aec3546ef1d1 | wikidoc | WalkAmerica | WalkAmerica
The March of Dimes WalkAmerica began in 1970 as the first charitable walking event in the United States.. WalkAmerica is held in 1,100 communities across the nation. Every year, 7 million compassionate people, including 20,000 company and family teams as well as national sponsors, participate. The event has raised more than $1.7 billion since 1970 to bring the March of Dimes closer to the day when all babies are born healthy and full term.
Proceeds help fund research to prevent premature births, birth defects and infant mortality. Every year, more half a million babies are born prematurely and more than 120,000 are born with serious birth defects in the United States .
Seventy-six cents of every dollar raised in WalkAmerica is spent on research and programs to help prevent premature birth, birth defects and infant mortality. | WalkAmerica
The March of Dimes WalkAmerica began in 1970 as the first charitable walking event in the United States.[1]. WalkAmerica is held in 1,100 communities across the nation. Every year, 7 million compassionate people, including 20,000 company and family teams as well as national sponsors, participate. The event has raised more than $1.7 billion since 1970 to bring the March of Dimes closer to the day when all babies are born healthy and full term. [1]
Proceeds help fund research to prevent premature births, birth defects and infant mortality. Every year, more half a million babies are born prematurely and more than 120,000 are born with serious birth defects in the United States [2].
Seventy-six cents of every dollar raised in WalkAmerica is spent on research and programs to help prevent premature birth, birth defects and infant mortality.[3] | https://www.wikidoc.org/index.php/WalkAmerica | |
2148279d29926a0f8bc67c1c3a01048b43e4b9b7 | wikidoc | Water model | Water model
In computational chemistry, classical water models are used for the simulation of water clusters, liquid water, and aqueous solutions with explicit solvent. These models use the approximations of molecular mechanics. Many different models have been proposed; they can be classified by the number of points used to define the model (atoms plus dummy sites), whether the structure is rigid or flexible, and whether the model includes polarization effects.
An alternative to the explicit water models is to use an implicit solvation model, also known as a continuum model.
# Simple water models
The simplest water models treat the water molecule as rigid and rely only on non-bonded interactions. The electrostatic interaction is modeled using Coulomb's law and the dispersion and repulsion forces using the Lennard-Jones potential. The potential for models such as TIP3P and TIP4P is represented by
where kC, the electrostatic constant, has a value of 332.1 Å·kcal/mol in the units commonly used in molecular modeling; qi are the partial charges relative to the charge of the electron; rij is the distance between two atoms or charged sites; and A and B are the Lennard-Jones parameters. The charged sites may be on the atoms or on dummy sites (such as lone pairs). In most water models, the Lennard-Jones term applies only to the interaction between the oxygen atoms.
The figure below shows the general shape of the 3- to 6-site water models. The exact geometric parameters (the OH distance and the HOH angle) vary depending on the model.
# 3-site
The simplest models have three interaction sites, corresponding to the three atoms of the water molecule. Each atom gets assigned a point charge, and the oxygen atom also gets the Lennard-Jones parameters. The 3-site models are very popular for molecular dynamics simulations because of their simplicity and computational efficiency. Most models use a rigid geometry matching the known geometry of the water molecule. An exception is the SPC model, which assumes an ideal tetrahedral shape (HOH angle of 109.47°) instead of the observed angle of 104.5°.
The table below lists the parameters for some 3-site models.
The SPC/E model adds an average polarization correction to the potential energy function:
where μ is the dipole of the effectively polarized water molecule (2.35 D for the SPC/E model), μ0 is the dipole moment of an isolated water molecule (1.85 D from experiment), and αi is an isotropic polarizability constant, with a value of 1.608 × 10−40 F m. Since the charges in the model are constant, this correction just results in adding 1.25 kcal/mol (5.22 kJ/mol) to the total energy. The SPC/E model results in a better density and diffusion constant than the SPC model.
The TIP3P model implemented in the CHARMM force field is a slightly modified version of the original. The difference lies in the Lennard-Jones parameters: unlike TIP3P, the CHARMM version of the model places Lennard-Jones parameters on the hydrogen atoms. The charges are not modified.
Other models:
- Fergunson (flex. SPC)
- CVFF (flex.)
# 4-site
The 4-site models place the negative charge on a dummy atom (labeled M in the figure) placed near the oxygen along the bisector of the HOH angle. This improves the electrostatic distribution around the water molecule. The first model to use this approach was the Bernal-Fowler model published in 1933, which may also be the earliest water model. However, the BF model doesn't reproduce well the bulk properties of water, such as density and heat of vaporization, and is therefore only of historical interest. This is a consequence of the parameterization method; newer models, developed after modern computers became available, were parameterized by running Metropolis Monte Carlo or molecular dynamics simulations and adjusting the parameters until the bulk properties are reproduced well enough.
The TIP4P model, first published in 1983, is widely implemented in computational chemistry software packages and often used for the simulation of biomolecular systems. There have been subsequent reparameterizations of the TIP4P model for specific uses: the TIP4P-Ew model, for use with Ewald summation methods; the TIP4P/Ice, for simulation of solid water ice; and TIP4P/2005, a general parameterization for simulating the entire phase diagram of water.
Others:
- TIP4PF (flexible)
# 5-site
The 5-site models place the negative charge on dummy atoms (labeled L) representing the lone pairs of the oxygen atom, with a tetrahedral-like geometry. An early model of these types was the BNS model of Ben-Naim and Stillinger, proposed in 1971, soon succeeded by the ST2 model of Stillinger and Rahman in 1974. Mainly due to their higher computational cost, five-site models were not developed much until 2000, when the TIP5P model of Mahoney and Jorgensen was published. When compared with earlier models, the TIP5P model results in improvements in the geometry for the water dimer, a more "tetrahedral" water structure that better reproduces the experimental radial distribution functions from neutron diffraction, and the temperature of maximum density of water. The TIP5P-E model is a reparameterization of TIP5P for use with Ewald sums.
Note, however, that the BNS and ST2 models do not use Coulomb's law directly for the electrostatic terms, but a modified version that is scaled down at short distances by multiplying it by the switching function S(r):
S(r_{ij}) =
\begin{cases}
\end{cases}
Therefore the RL and RU parameters only apply to BNS and ST2.
# 6-site
A 6-site model that combines all the sites of the 4- and 5-site models was developed by Nada and van der Eerden. It was found to reproduce the structure and melting of ice better than other models.
# Other
- MB model. A more abstract model resembling the Mercedes-Benz logo that reproduces some features of water in two-dimensional systems. It is not used as such for simulations of "real" (i.e., three-dimensional) systems, but it is useful for qualitative studies and for educational purposes.
- Coarse-grained models. One- and two-site models of water have also been developed.
# Computational cost
The computational cost of a water simulation increases with the number of interaction sites in the water model. The CPU time is approximately proportional to the number of interatomic distances that need to be computed. For the 3-site model, 9 distances are required for each pair of water molecules (every atom of one molecule against every atom of the other molecule, or 3 × 3). For the 4-site model, 10 distances are required (every charged site with every charged site, plus the O-O interaction, or 3 × 3 + 1). For the 5-site model, 17 distances are required (4 × 4 + 1). Finally, for the 6-site model, 26 distances are required (5 × 5 + 1).
When using rigid water models in molecular dynamics, there is an additional cost associated with keeping the structure constrained, using constraint algorithms (although with bond lengths constrained it is often possible to increase the time step). | Water model
In computational chemistry, classical water models are used for the simulation of water clusters, liquid water, and aqueous solutions with explicit solvent. These models use the approximations of molecular mechanics. Many different models have been proposed; they can be classified by the number of points used to define the model (atoms plus dummy sites), whether the structure is rigid or flexible, and whether the model includes polarization effects.
An alternative to the explicit water models is to use an implicit solvation model, also known as a continuum model.
# Simple water models
The simplest water models treat the water molecule as rigid and rely only on non-bonded interactions. The electrostatic interaction is modeled using Coulomb's law and the dispersion and repulsion forces using the Lennard-Jones potential. The potential for models such as TIP3P and TIP4P is represented by
</math>
where kC, the electrostatic constant, has a value of 332.1 Å·kcal/mol in the units commonly used in molecular modeling; qi are the partial charges relative to the charge of the electron; rij is the distance between two atoms or charged sites; and A and B are the Lennard-Jones parameters. The charged sites may be on the atoms or on dummy sites (such as lone pairs). In most water models, the Lennard-Jones term applies only to the interaction between the oxygen atoms.
The figure below shows the general shape of the 3- to 6-site water models. The exact geometric parameters (the OH distance and the HOH angle) vary depending on the model.
# 3-site
The simplest models have three interaction sites, corresponding to the three atoms of the water molecule. Each atom gets assigned a point charge, and the oxygen atom also gets the Lennard-Jones parameters. The 3-site models are very popular for molecular dynamics simulations because of their simplicity and computational efficiency. Most models use a rigid geometry matching the known geometry of the water molecule. An exception is the SPC model, which assumes an ideal tetrahedral shape (HOH angle of 109.47°) instead of the observed angle of 104.5°.
The table below lists the parameters for some 3-site models.
The SPC/E model adds an average polarization correction to the potential energy function:
</math>
where μ is the dipole of the effectively polarized water molecule (2.35 D for the SPC/E model), μ0 is the dipole moment of an isolated water molecule (1.85 D from experiment), and αi is an isotropic polarizability constant, with a value of 1.608 × 10−40 F m. Since the charges in the model are constant, this correction just results in adding 1.25 kcal/mol (5.22 kJ/mol) to the total energy. The SPC/E model results in a better density and diffusion constant than the SPC model.
The TIP3P model implemented in the CHARMM force field is a slightly modified version of the original. The difference lies in the Lennard-Jones parameters: unlike TIP3P, the CHARMM version of the model places Lennard-Jones parameters on the hydrogen atoms. The charges are not modified.[5]
Other models:
- Fergunson (flex. SPC)
- CVFF (flex.)
# 4-site
The 4-site models place the negative charge on a dummy atom (labeled M in the figure) placed near the oxygen along the bisector of the HOH angle. This improves the electrostatic distribution around the water molecule. The first model to use this approach was the Bernal-Fowler model published in 1933, which may also be the earliest water model. However, the BF model doesn't reproduce well the bulk properties of water, such as density and heat of vaporization, and is therefore only of historical interest. This is a consequence of the parameterization method; newer models, developed after modern computers became available, were parameterized by running Metropolis Monte Carlo or molecular dynamics simulations and adjusting the parameters until the bulk properties are reproduced well enough.
The TIP4P model, first published in 1983, is widely implemented in computational chemistry software packages and often used for the simulation of biomolecular systems. There have been subsequent reparameterizations of the TIP4P model for specific uses: the TIP4P-Ew model, for use with Ewald summation methods; the TIP4P/Ice, for simulation of solid water ice; and TIP4P/2005, a general parameterization for simulating the entire phase diagram of water.
Others:
- TIP4PF (flexible)
# 5-site
The 5-site models place the negative charge on dummy atoms (labeled L) representing the lone pairs of the oxygen atom, with a tetrahedral-like geometry. An early model of these types was the BNS model of Ben-Naim and Stillinger, proposed in 1971, soon succeeded by the ST2 model of Stillinger and Rahman in 1974. Mainly due to their higher computational cost, five-site models were not developed much until 2000, when the TIP5P model of Mahoney and Jorgensen was published. When compared with earlier models, the TIP5P model results in improvements in the geometry for the water dimer, a more "tetrahedral" water structure that better reproduces the experimental radial distribution functions from neutron diffraction, and the temperature of maximum density of water. The TIP5P-E model is a reparameterization of TIP5P for use with Ewald sums.
Note, however, that the BNS and ST2 models do not use Coulomb's law directly for the electrostatic terms, but a modified version that is scaled down at short distances by multiplying it by the switching function S(r):
S(r_{ij}) =
\begin{cases}
\end{cases}
</math>
Therefore the RL and RU parameters only apply to BNS and ST2.
# 6-site
A 6-site model that combines all the sites of the 4- and 5-site models was developed by Nada and van der Eerden[14]. It was found to reproduce the structure and melting of ice better than other models.
# Other
- MB model. A more abstract model resembling the Mercedes-Benz logo that reproduces some features of water in two-dimensional systems. It is not used as such for simulations of "real" (i.e., three-dimensional) systems, but it is useful for qualitative studies and for educational purposes.[15]
- Coarse-grained models. One- and two-site models of water have also been developed.[16]
# Computational cost
The computational cost of a water simulation increases with the number of interaction sites in the water model. The CPU time is approximately proportional to the number of interatomic distances that need to be computed. For the 3-site model, 9 distances are required for each pair of water molecules (every atom of one molecule against every atom of the other molecule, or 3 × 3). For the 4-site model, 10 distances are required (every charged site with every charged site, plus the O-O interaction, or 3 × 3 + 1). For the 5-site model, 17 distances are required (4 × 4 + 1). Finally, for the 6-site model, 26 distances are required (5 × 5 + 1).
When using rigid water models in molecular dynamics, there is an additional cost associated with keeping the structure constrained, using constraint algorithms (although with bond lengths constrained it is often possible to increase the time step). | https://www.wikidoc.org/index.php/Water_model | |
29e29c4ee4b435cc4c555b718cb1f7683256aa68 | wikidoc | Water tower | Water tower
A water tower or elevated water tank is a very large tank constructed for the purpose of holding a supply of water at a height sufficient to pressurize a water supply system. Many water towers were constructed during the industrial revolution and some of these are now considered architectural landmarks and monuments and may not be demolished. Some are converted to apartments or exclusive penthouses.
In certain areas, such as New York City, smaller water towers are constructed for individual buildings.
# Construction
A typical water tower is constructed of steel, reinforced or prestressed concrete or bricks. It is usually spherical or cylindrical and is approximately 50 feet (16 metres) in diameter. It typically has a height of approximately 120 feet (40 metres).
# Purpose
The users of the water supply (a town, factory, or just a building) need to have water pressure to maintain the safety of the water supply. If a water supply is not pressurized sufficiently, several things can happen:
- Water may not reach the upper floors of a building;
- Water may not spray from a tap with sufficient flow
- Without a water tower, parts of gravity flow water supply systems in hilly areas may be subject to negative pressures (see siphon). Negative pressure in the system may cause shallow groundwater to be sucked into a leaky water supply system, polluting it with microorganisms, dirt, sand, fertilizers, and any other toxic contaminants that may be in the groundwater;
- The water towers supply water even during power cuts because they use gravity to pressurize the water pipes in people's homes, although it cannot supply water for a long time without electricity because electricity is needed to pump water up into the tower.
- A further purpose is that a water tower serves as a reservoir to help with water needs during peak usage times. The water level in the tower typically falls during the peak usage hours of the day, and then pumps fill it back up during the night. This process also keeps the water from freezing in cold weather, since it is constantly being used and refilled.
# Operation
The height of the tower provides the hydrostatic pressure for the water supply system, and it may be supplemented with a pump. The volume of the reservoir and diameter of the piping provide and sustain flow rate. However, relying on a pump to provide pressure is expensive; to keep up with varying demand, the pump would have to provide a constantly varying output pressure (and thus need an expensive control system) and it would have to be sized sufficiently to give the same pressure at high flow rates.
Very high flow rates are needed when fighting fires. With a water tower present, pumps can be sized for average demand, not peak demand; the tower can provide water pressure during the day and the pumps can refill the water tower at night when demand is very low.
# Decoration
Water towers can be surrounded by ornate coverings including fancy brickwork, a large ivy-covered trellis or it can be simply painted. Some city water towers had the name of the city painted in large letters on the roof, as a navigational aid to aviators. Sometimes the decoration can be humorous, as Granger, Iowa has two water towers, labeled HOT and COLD. The The House in the Clouds in Thorpeness was built to resemble a house in order to disguise the eyesore, whilst the lower floors were used for accommodation. When the town was connected to the mains water supply, the tank was dismantled and converted to additional living space.
Sapp Bros. truck stops uses a water tower with a handle and spout -- looking like a coffee pot -- as the company logo. Many of their facilities have thus-decorated actual water towers (presumably non-functional) on-site.
The first and original "Mushroom" -- Svampen in Swedish -- was built in Örebro in Sweden in the early 1950s and later copies were built around the world including Saudi-Arabia and Kuwait.
# Uses today
Water towers are very common in India, where the electricity supply is erratic in most places. Water tanks are used atop houses and multi-story houses to store water from erratic supplies.
In many countries, water towers have been taken out of the water supply system and replaced by pumps alone. Water towers are often regarded to be the monuments of civil engineering. Some are rejuvenated and converted to serve modern purposes. A good example of the latter is Wieża Ciśnień in Wroclaw, Poland.
# Railway use
All railways making use of steam locomotives require a means of replenishing the locomotive's water tank. This is most commonly achieved by means of a water tower feeding one or more water cranes, usually located at stations and locomotive sheds.
# Further uses
Some water towers are also used as observation towers. There are even water towers with restaurants, such as the Goldbergturm in Sindelfingen, Germany. It is also common to use water towers as the location of transmission mechanisms in the UHF range with small power, for instance for closed rural broadcasting service, portable radio, or cellular telephone service.
# New York City
In the 1800s, New York City required that all buildings higher than 6 stories be equipped with a rooftop water tower. This was necessary to prevent the need for excessively high pressures at lower elevations, which could burst pipes. In modern times, the towers have become fashionable in some circles. As of 2006, the neighborhood of Tribeca requires water towers on all buildings, whether or not they are being used. Two companies in New York build water towers, both of which are family businesses in operation since the 1800s.
The original water tower builders were barrel makers who expanded their craft to meet a modern need as buildings in the city grew taller in height. Even today, no sealant is used to hold the water in. Tank walls are held together with cables but leak through every gap when first filled. As the wood swells, the gaps close and become impermeable.
The rooftop tanks store 5,000 to 10,000 gallons of water until it is needed in the building below. The upper portion of water is skimmed off the top for everyday use while the water in the bottom of the tank is held in reserve to fight fire. When the water drops below a certain level, a pump is triggered and the tank is refilled.
# Famous towers
Famous water towers in the USA include:
- Chicago Water Tower
- Volunteer Park Water Tower, Capitol Hill, Seattle, Washington
- Warner Bros. Studios Water Tower, Burbank, California (In the animated TV series Animaniacs, it was used to incarcerate the characters Yakko, Wakko, and Dot.
- Peachoid next to I-85 on the edge of Gaffney, South Carolina
- Earful Tower at Disney-MGM Studios
- Florence Y'all Water Tower in Florence, Kentucky
- Union Water Sphere in Union Township, New Jersey
Famous water towers in the UK include:
- Dock Tower in Grimsby
- 'House in the Clouds' in Thorpeness, Suffolk
- Jumbo in Colchester, Essex
Famous water towers in Sweden include:
- Svampen in Örebro | Water tower
A water tower or elevated water tank is a very large tank constructed for the purpose of holding a supply of water at a height sufficient to pressurize a water supply system. Many water towers were constructed during the industrial revolution and some of these are now considered architectural landmarks and monuments and may not be demolished. Some are converted to apartments or exclusive penthouses.
In certain areas, such as New York City, smaller water towers are constructed for individual buildings.
# Construction
A typical water tower is constructed of steel, reinforced or prestressed concrete or bricks. It is usually spherical or cylindrical and is approximately 50 feet (16 metres) in diameter. It typically has a height of approximately 120 feet (40 metres).
# Purpose
The users of the water supply (a town, factory, or just a building) need to have water pressure to maintain the safety of the water supply. If a water supply is not pressurized sufficiently, several things can happen:
- Water may not reach the upper floors of a building;
- Water may not spray from a tap with sufficient flow
- Without a water tower, parts of gravity flow water supply systems in hilly areas may be subject to negative pressures (see siphon). Negative pressure in the system may cause shallow groundwater to be sucked into a leaky water supply system, polluting it with microorganisms, dirt, sand, fertilizers, and any other toxic contaminants that may be in the groundwater;
- The water towers supply water even during power cuts because they use gravity to pressurize the water pipes in people's homes, although it cannot supply water for a long time without electricity because electricity is needed to pump water up into the tower.
- A further purpose is that a water tower serves as a reservoir to help with water needs during peak usage times. The water level in the tower typically falls during the peak usage hours of the day, and then pumps fill it back up during the night. This process also keeps the water from freezing in cold weather, since it is constantly being used and refilled.
# Operation
The height of the tower provides the hydrostatic pressure for the water supply system, and it may be supplemented with a pump. The volume of the reservoir and diameter of the piping provide and sustain flow rate. However, relying on a pump to provide pressure is expensive; to keep up with varying demand, the pump would have to provide a constantly varying output pressure (and thus need an expensive control system) and it would have to be sized sufficiently to give the same pressure at high flow rates.
Very high flow rates are needed when fighting fires. With a water tower present, pumps can be sized for average demand, not peak demand; the tower can provide water pressure during the day and the pumps can refill the water tower at night when demand is very low.
# Decoration
Water towers can be surrounded by ornate coverings including fancy brickwork, a large ivy-covered trellis or it can be simply painted. Some city water towers had the name of the city painted in large letters on the roof, as a navigational aid to aviators. Sometimes the decoration can be humorous, as Granger, Iowa has two water towers, labeled HOT and COLD. The The House in the Clouds in Thorpeness was built to resemble a house in order to disguise the eyesore, whilst the lower floors were used for accommodation. When the town was connected to the mains water supply, the tank was dismantled and converted to additional living space.
Sapp Bros. truck stops uses a water tower with a handle and spout -- looking like a coffee pot -- as the company logo. Many of their facilities have thus-decorated actual water towers (presumably non-functional) on-site.
The first and original "Mushroom" -- Svampen in Swedish -- was built in Örebro in Sweden in the early 1950s and later copies were built around the world including Saudi-Arabia and Kuwait.[citation needed]
# Uses today
Water towers are very common in India, where the electricity supply is erratic in most places. [1] Water tanks are used atop houses and multi-story houses to store water from erratic supplies.
In many countries, water towers have been taken out of the water supply system and replaced by pumps alone. Water towers are often regarded to be the monuments of civil engineering. Some are rejuvenated and converted to serve modern purposes. A good example of the latter is Wieża Ciśnień in Wroclaw, Poland.[citation needed]
# Railway use
All railways making use of steam locomotives require a means of replenishing the locomotive's water tank. This is most commonly achieved by means of a water tower feeding one or more water cranes, usually located at stations and locomotive sheds.
Template:Sect-stub
# Further uses
Some water towers are also used as observation towers. There are even water towers with restaurants, such as the Goldbergturm in Sindelfingen, Germany. It is also common to use water towers as the location of transmission mechanisms in the UHF range with small power, for instance for closed rural broadcasting service, portable radio, or cellular telephone service.
# New York City
In the 1800s, New York City required that all buildings higher than 6 stories be equipped with a rooftop water tower. This was necessary to prevent the need for excessively high pressures at lower elevations, which could burst pipes. In modern times, the towers have become fashionable in some circles. As of 2006, the neighborhood of Tribeca requires water towers on all buildings, whether or not they are being used. Two companies in New York build water towers, both of which are family businesses in operation since the 1800s.[1]
The original water tower builders were barrel makers who expanded their craft to meet a modern need as buildings in the city grew taller in height. Even today, no sealant is used to hold the water in. Tank walls are held together with cables but leak through every gap when first filled. As the wood swells, the gaps close and become impermeable.[2]
The rooftop tanks store 5,000 to 10,000 gallons of water until it is needed in the building below. The upper portion of water is skimmed off the top for everyday use while the water in the bottom of the tank is held in reserve to fight fire. When the water drops below a certain level, a pump is triggered and the tank is refilled.[3]
Template:Seealso
Template:Sect-stub
# Famous towers
Famous water towers in the USA include:
- Chicago Water Tower
- Volunteer Park Water Tower, Capitol Hill, Seattle, Washington
- Warner Bros. Studios Water Tower, Burbank, California (In the animated TV series Animaniacs, it was used to incarcerate the characters Yakko, Wakko, and Dot.
- Peachoid next to I-85 on the edge of Gaffney, South Carolina
- Earful Tower at Disney-MGM Studios
- Florence Y'all Water Tower in Florence, Kentucky
- Union Water Sphere in Union Township, New Jersey
Famous water towers in the UK include:
- Dock Tower in Grimsby
- 'House in the Clouds' in Thorpeness, Suffolk
- Jumbo in Colchester, Essex
Famous water towers in Sweden include:
- Svampen in Örebro | https://www.wikidoc.org/index.php/Water_tower | |
7b87d9e0d4d54a57368b3a3f57ae9033ccdaeb98 | wikidoc | Water vapor | Water vapor
Water vapor or water vapour (see spelling differences), also aqueous vapor, is the gas phase of water. Water vapor is one state of the water cycle within the hydrosphere. Water vapor can be produced from the evaporation of liquid water or from the sublimation of ice. Under normal atmospheric conditions, water vapor is continuously generated by evaporation and removed by condensation.
# General properties of water vapor
## Evaporation/sublimation
Whenever a water molecule leaves a surface, it is said to have evaporated. Each individual water molecule which transitions between a more associated (liquid) and a less associated (vapor/gas) state does so through the absorption or release of kinetic energy. The aggregate measurement of this kinetic energy transfer is defined as thermal energy and occurs only when there is differential in the temperature of the water molecules. Liquid water that becomes water vapor takes a parcel of heat with it, in a process called evaporative cooling. The amount of water vapor in the air determines how fast each molecule will return back to the surface. When a net evaporation occurs, the body of water will undergo a net cooling directly related to the loss of water.
In the US, the National Weather Service measures the actual rate of evaporation from a standardized "pan" open water surface outdoors, at various locations nationwide. Others do likewise around the world. The US data is collected and compiled into an annual evaporation map. The measurements range from under 30 to over 120 inches per year. Formulas for calculating the rate of evaporation from a water surface such as a swimming pool of can be found here and here
Evaporative cooling is restricted by atmospheric conditions. Humidity is the amount of water vapor in the air. The vapor content of air is measured with devices known as hygrometers. The measurements are usually expressed as specific humidity or percent relative humidity. The temperatures of the atmosphere and the water surface determine the equilibrium vapor pressure; 100% relative humidity occurs when the partial pressure of water vapor is equal to the equilibrium vapor pressure. This condition is often referred to as complete saturation. Humidity ranges from 0 gram per cubic metre in dry air to 30 grams per cubic metre (0.03 ounce per cubic foot) when the vapour is saturated at 30 °C.
(See also Absolute Humidity table)
Another form of evaporation is sublimation, by which water molecules become gaseous directly from ice without first becoming liquid water. Sublimation accounts for the slow mid-winter disappearance of ice and snow at temperatures too low to cause melting.
## Condensation
Water vapor will only condense onto another surface when that surface is cooler than the temperature of the water vapor, or when the water vapor equilibrium in air has been exceeded. When water vapor condenses onto a surface, a net warming occurs on that surface. The water molecule brings a parcel of heat with it. In turn, the temperature of the atmosphere drops slightly. In the atmosphere, condensation produces clouds, fog and precipitation (usually only when facilitated by cloud condensation nuclei). The dew point of an air parcel is the temperature to which it must cool before water vapor in the air begins to condense.
Also, a net condensation of water vapor occurs on surfaces when the temperature of the surface is at or below the dew point temperature of the atmosphere. Deposition, the direct formation of ice from water vapor, is a type of condensation. Frost and snow are examples of deposition.
## Water vapor density
Water vapor is lighter or less dense than dry air. At equivalent temperatures it is buoyant with respect to dry air.
### Water vapor and dry air density calculations at 0°C
The molecular mass or weight of water is 18.02g/mol, as calculated from the sum of the atomic masses of its constituent atoms.
The average molecular mass of air (Approx. 79% nitrogen, N2; 21% Oxygen, 02) is 28.57g/mol at standard temperature and pressure (STP).
Using Avogadro's Law and the ideal gas law, water vapor and air will have a molar volume of 22.414 litre/mol at STP. A molar mass of air and water vapour occupy the same volume
-f 22.414 litres. The density (mass/volume) of water vapor is 0.804g/litre, which is significantly less than that of dry air at 1.27g/litre at STP.
Note that STP conditions include a temperature of 0°C, at which the ability of water to become vapor is very restricted. Its concentration in air is very low at 0°C. The red line on the chart to the right is the maximum concentration of water vapor expected for a given temperature. The water vapor concentration increases significantly as the temperature rises, approaching 100% (steam, pure water vapor) at 100°C. However the difference in densities between air and water vapour would still exist.
### Air and water vapor density interactions at equal temperatures
At the same temperature, a column of dry air will be denser or heavier than a column of air containing any water vapor. Thus, any volume of dry air will sink if placed in a larger volume of moist air. Also, a volume of moist air will rise or be buoyant if placed in a larger region of dry air. As the temperature rises the proportion water vapor in the air increases, its buoyancy will become larger. This increase in buoyancy can have a signicant atmospheric impact, giving rise to powerful, moisture rich, upward air currents when the air temperature and sea temperature reaches 25°C or above. This phenomenon provides a significant motivating force for cyclonic and anticyconic weather systems (tornados and hurricanes).
## Water vapour and respiration or breathing
Water vapor's contribution to the pressure increases as its concentration increases. Its partial pressure contribution to air pressure increases, lowering the partial pressure contribution of the other atmospheric gases (Dalton's Law). The total air pressure must remain constant. The presence of water vapor in the air naturally dilutes or displaces the other air components as its concentration increases.
This can have an effect on respiration, in very warm air (35°C). The proportion of water vapor is significant enough to give rise to the stuffiness that can be experienced in humid jungle conditions or in poorly air conditioned buildings.
## General discussion
The amount of water vapor in an atmosphere is constrained by the restrictions of partial pressures and temperature. Dew point temperature and relative humidity act as guidelines for the process of water vapor in the water cycle. Energy input, such as sunlight, can trigger more evaporation on an ocean surface or more sublimation on a chunk of ice on top of a mountain. The balance between condensation and evaporation gives the quantity called vapor partial pressure.
The maximum partial pressure (saturation pressure) of water vapor in air varies with temperature of the air and water vapor mixture. A variety of empirical formulas exist for this quantity; the most used reference formula is the Goff-Gratch equation for the SVP over liquid water:
The formula is valid from about −50 to 102 °C; however there are a very limited number of measurements of the vapor pressure of water over supercooled liquid water.
Under adverse conditions, such as when the boiling temperature of water is reached, a net evaporation will always occur during standard atmospheric conditions regardless of the percent of relative humidity. This immediate process will dispel massive amounts of water vapor into a cooler atmosphere.
Exhaled air is almost fully at equilibrium with water vapor at the body temperature. In the cold air the exhaled vapor quickly condenses, thus showing up as a fog or mist of water droplets and as condensation or frost on surfaces.
Controlling water vapor in air is a key concern in the heating, ventilating, and air-conditioning (HVAC) industry. Thermal comfort depends on the moist air conditions. Non-human comfort situations are called refrigeration, and also are affected by water vapor. For example many food stores, like supermarkets, utilize open chiller cabinets, or food cases, which can significantly lower the water vapor pressure (lowering humidity). This practice delivers several benefits as well as problems.
# Water vapor in Earth's atmosphere
Gaseous water represents a small but environmentally significant constituent of the atmosphere. Approximately 99.99% of it is contained in the troposphere. The condensation of water vapor to the liquid or ice phase is responsible for clouds, rain, snow, and other precipitation, all of which count among the most significant elements of what we experience as weather. Less obviously, the latent heat of vaporization, which is released to the atmosphere whenever condensation occurs, is one of the most important terms in the atmospheric energy budget on both local and global scales. For example, latent heat release in atmospheric convection is directly responsible for powering destructive storms such as tropical cyclones and severe thunderstorms. Water vapor is also a potent greenhouse gas. Because the water vapor content of the atmosphere is expected to greatly increase in response to warmer temperatures, there is the potential for a water vapor feedback that could amplify the expected climate warming effect due to increased carbon dioxide alone. However, it is less clear how cloudiness would respond to a warming climate; depending on the nature of the response, clouds could either further amplify or partly mitigate the water vapor feedback.
Fog and clouds form through condensation around cloud condensation nuclei. In the absence of nuclei, condensation will only occur at much lower temperatures. Under persistent condensation or deposition, cloud droplets or snowflakes form, which precipitate when they reach a critical mass.
The average residence time of water molecules in the troposphere is about 10 days. Water depleted by precipitation is replenished by evaporation from the seas, lakes, rivers and the transpiration of plants, and other biological and geological processes.
Measurements of vapor concentration are expressed as specific humidity or percent relative humidity. The annual mean global concentration of water vapor would yield about 25 mm of liquid water over the entire surface of the Earth if it were to instantly condense. However, the mean annual precipitation for the planet is about 1 meter, which indicates a rapid turnover of water in the air.
The abundance of gases emitted by volcanoes varies considerably from volcano to volcano. However, water vapor is consistently the most common volcanic gas, normally comprising more than 60% of total emissions during a subaerial volcanic eruption.
## Radar and satellite imaging
Because water molecules absorb microwaves and other radio wave frequencies, water in the atmosphere attenuates radar signals. In addition, atmospheric water will reflect and refract signals to an extent that depends on whether it is vapor, liquid or solid.
Generally, radar signals lose strength progressively the farther they travel through the troposphere. Different frequencies attenuate at different rates, such that some components of air are opaque to some frequencies and transparent to others. Radio waves used for broadcasting and other communication experience the same effect.
Water vapor reflects radar to a less extent than do water's other two phases. In the form of drops and ice crystals, water acts as a prism, which it does not do as an individual molecule; however, the existence of water vapor in the atmosphere causes the atmosphere to act as a giant prism.
A comparison of GOES-12 satellite images shows the distribution of atmospheric water vapor relative to the oceans, clouds and continents of the Earth. Vapor surrounds the planet but is unevenly distributed.
## Lightning generation
Water vapor plays a key role in lightning production in the atmosphere. From cloud physics, usually, clouds are the real generators of static charge as found in Earth's atmosphere. But the ability, or caterbility of clouds to hold massive amounts of electrical energy is directly related to the amount of water vapor present in the local system.
The amount of water vapor directly controls the permittivity of the air. During times of low humidity, static discharge is quick and easy. During times of higher humidity, fewer static discharges occur. However, permittivity and capacitance work hand in hand to produce the megawatt outputs of lightning.
After a cloud, for instance, has started its way to becoming a lightning generator, atmospheric water vapor acts as a substance (or insulator ) that decreases the ability of the cloud to discharge its electrical energy. Over a certain amount of time, if the cloud continues to generate and store more static electricity, the barrier that was created by the atmospheric water vapor will ultimately break down from the stored electrical potential energy. This energy will be released to a locally, opposite charged region in the form of lightning. The strength of each discharge is directly related to the atmospheric permittivity, capacitance, and the source's charge generating ability.
See also, Van de Graaff generator.
## Extraterrestrial water vapor
The brilliance of comet tails comes largely from water vapor. On approach to the sun, the ice many comets carry sublimates to vapor, which reflects light from the sun. Knowing a comet's distance from the sun, astronomers may deduce a comet's water content from its brilliance. Bright tails in cold and distant comets suggests carbon monoxide sublimation.
Scientists studying Mars hypothesize that if water moves about the planet, it does so as vapor. Most of the water on Mars appears to exist as ice at the northern pole. During Mars' summer, this ice sublimates, perhaps enabling massive seasonal storms to convey significant amounts of water toward the equator.
A star called CW Leonis was found to have a ring of vast quantities of water vapor circling the aging, massive star. A NASA satellite designed to study chemicals in interstellar gas clouds, made the discovery with an onboard spectrometer. Most likely, "the water vapor was vaporized from the surfaces of orbiting comets."
Spectroscopic analysis of HD 209458 b, an extrasolar planet in the constellation Pegasus, provides the first evidence of atmospheric water vapor beyond the Solar System.
# Scientific Discrepancies, Confounding factors and limits of knowledge
Since water vapor is very common, it has been studied and written about from many perspectives. As a working knowledge has grown and developed within apparently unrelated fields several discrepancies in understanding may be encountered. These discrepancies often arise from an inability to rigidly determine either a Volumetric or Gravimetric basis of study ; and/or use of constants inappropriate for the conditions being observed.
Many scientific studies view water vapor as a Confounding variable (preventing Ceteris paribus, also 'lurking varible') due to its complex nature, this becomes especially true when the study observes significant variation in water vapor quantities, over time and/or location.
It is for the reasons above that this remains a particularly tricky and sometimes controversial factor in many fields of science, whether storage of foods or ancient artefacts, Thermodynamics or Climate Change. | Water vapor
Water vapor or water vapour (see spelling differences), also aqueous vapor, is the gas phase of water. Water vapor is one state of the water cycle within the hydrosphere.[2] Water vapor can be produced from the evaporation of liquid water or from the sublimation of ice. Under normal atmospheric conditions,[3] water vapor is continuously generated by evaporation and removed by condensation.
# General properties of water vapor
## Evaporation/sublimation
Whenever a water molecule leaves a surface, it is said to have evaporated. Each individual water molecule which transitions between a more associated (liquid) and a less associated (vapor/gas) state does so through the absorption or release of kinetic energy. The aggregate measurement of this kinetic energy transfer is defined as thermal energy and occurs only when there is differential in the temperature of the water molecules. Liquid water that becomes water vapor takes a parcel of heat with it, in a process called evaporative cooling.[4] The amount of water vapor in the air determines how fast each molecule will return back to the surface. When a net evaporation occurs, the body of water will undergo a net cooling directly related to the loss of water.[5]
In the US, the National Weather Service measures the actual rate of evaporation from a standardized "pan" open water surface outdoors, at various locations nationwide. Others do likewise around the world. The US data is collected and compiled into an annual evaporation map.[1] The measurements range from under 30 to over 120 inches per year. Formulas for calculating the rate of evaporation from a water surface such as a swimming pool of can be found here[2] and here[3]
Evaporative cooling is restricted by atmospheric conditions. Humidity is the amount of water vapor in the air. The vapor content of air is measured with devices known as hygrometers. The measurements are usually expressed as specific humidity or percent relative humidity. The temperatures of the atmosphere and the water surface determine the equilibrium vapor pressure; 100% relative humidity occurs when the partial pressure of water vapor is equal to the equilibrium vapor pressure. This condition is often referred to as complete saturation. Humidity ranges from 0 gram per cubic metre in dry air to 30 grams per cubic metre (0.03 ounce per cubic foot) when the vapour is saturated at 30 °C.[4]
(See also Absolute Humidity table)
Another form of evaporation is sublimation, by which water molecules become gaseous directly from ice without first becoming liquid water. Sublimation accounts for the slow mid-winter disappearance of ice and snow at temperatures too low to cause melting.
## Condensation
Water vapor will only condense onto another surface when that surface is cooler than the temperature of the water vapor, or when the water vapor equilibrium in air has been exceeded. When water vapor condenses onto a surface, a net warming occurs on that surface.[6] The water molecule brings a parcel of heat with it. In turn, the temperature of the atmosphere drops slightly.[7] [8] In the atmosphere, condensation produces clouds, fog and precipitation (usually only when facilitated by cloud condensation nuclei). The dew point of an air parcel is the temperature to which it must cool before water vapor in the air begins to condense.
Also, a net condensation of water vapor occurs on surfaces when the temperature of the surface is at or below the dew point temperature of the atmosphere. Deposition, the direct formation of ice from water vapor, is a type of condensation. Frost and snow are examples of deposition.
## Water vapor density
Water vapor is lighter or less dense than dry air. At equivalent temperatures it is buoyant with respect to dry air.
### Water vapor and dry air density calculations at 0°C
The molecular mass or weight of water is 18.02g/mol, as calculated from the sum of the atomic masses of its constituent atoms.
The average molecular mass of air (Approx. 79% nitrogen, N2; 21% Oxygen, 02) is 28.57g/mol at standard temperature and pressure (STP).
Using Avogadro's Law and the ideal gas law, water vapor and air will have a molar volume of 22.414 litre/mol at STP. A molar mass of air and water vapour occupy the same volume
of 22.414 litres. The density (mass/volume) of water vapor is 0.804g/litre, which is significantly less than that of dry air at 1.27g/litre at STP.
Note that STP conditions include a temperature of 0°C, at which the ability of water to become vapor is very restricted. Its concentration in air is very low at 0°C. The red line on the chart to the right is the maximum concentration of water vapor expected for a given temperature. The water vapor concentration increases significantly as the temperature rises, approaching 100% (steam, pure water vapor) at 100°C. However the difference in densities between air and water vapour would still exist.
### Air and water vapor density interactions at equal temperatures
At the same temperature, a column of dry air will be denser or heavier than a column of air containing any water vapor. Thus, any volume of dry air will sink if placed in a larger volume of moist air. Also, a volume of moist air will rise or be buoyant if placed in a larger region of dry air. As the temperature rises the proportion water vapor in the air increases, its buoyancy will become larger. This increase in buoyancy can have a signicant atmospheric impact, giving rise to powerful, moisture rich, upward air currents when the air temperature and sea temperature reaches 25°C or above. This phenomenon provides a significant motivating force for cyclonic and anticyconic weather systems (tornados and hurricanes).
## Water vapour and respiration or breathing
Water vapor's contribution to the pressure increases as its concentration increases. Its partial pressure contribution to air pressure increases, lowering the partial pressure contribution of the other atmospheric gases (Dalton's Law). The total air pressure must remain constant. The presence of water vapor in the air naturally dilutes or displaces the other air components as its concentration increases.
This can have an effect on respiration, in very warm air (35°C). The proportion of water vapor is significant enough to give rise to the stuffiness that can be experienced in humid jungle conditions or in poorly air conditioned buildings.
## General discussion
The amount of water vapor in an atmosphere is constrained by the restrictions of partial pressures and temperature. Dew point temperature and relative humidity act as guidelines for the process of water vapor in the water cycle. Energy input, such as sunlight, can trigger more evaporation on an ocean surface or more sublimation on a chunk of ice on top of a mountain. The balance between condensation and evaporation gives the quantity called vapor partial pressure[9].
The maximum partial pressure (saturation pressure) of water vapor in air varies with temperature of the air and water vapor mixture. A variety of empirical formulas exist for this quantity; the most used reference formula is the Goff-Gratch equation for the SVP over liquid water:
The formula is valid from about −50 to 102 °C; however there are a very limited number of measurements of the vapor pressure of water over supercooled liquid water.[10]
Under adverse conditions, such as when the boiling temperature of water is reached, a net evaporation will always occur during standard atmospheric conditions regardless of the percent of relative humidity. This immediate process will dispel massive amounts of water vapor into a cooler atmosphere.
Exhaled air is almost fully at equilibrium with water vapor at the body temperature. In the cold air the exhaled vapor quickly condenses, thus showing up as a fog or mist of water droplets and as condensation or frost on surfaces.
Controlling water vapor in air is a key concern in the heating, ventilating, and air-conditioning (HVAC) industry. Thermal comfort depends on the moist air conditions. Non-human comfort situations are called refrigeration, and also are affected by water vapor. For example many food stores, like supermarkets, utilize open chiller cabinets, or food cases, which can significantly lower the water vapor pressure (lowering humidity). This practice delivers several benefits as well as problems.
# Water vapor in Earth's atmosphere
Gaseous water represents a small but environmentally significant constituent of the atmosphere. Approximately 99.99% of it is contained in the troposphere. The condensation of water vapor to the liquid or ice phase is responsible for clouds, rain, snow, and other precipitation, all of which count among the most significant elements of what we experience as weather. Less obviously, the latent heat of vaporization, which is released to the atmosphere whenever condensation occurs, is one of the most important terms in the atmospheric energy budget on both local and global scales. For example, latent heat release in atmospheric convection is directly responsible for powering destructive storms such as tropical cyclones and severe thunderstorms. Water vapor is also a potent greenhouse gas. Because the water vapor content of the atmosphere is expected to greatly increase in response to warmer temperatures, there is the potential for a water vapor feedback that could amplify the expected climate warming effect due to increased carbon dioxide alone. However, it is less clear how cloudiness would respond to a warming climate; depending on the nature of the response, clouds could either further amplify or partly mitigate the water vapor feedback.
Fog and clouds form through condensation around cloud condensation nuclei. In the absence of nuclei, condensation will only occur at much lower temperatures. Under persistent condensation or deposition, cloud droplets or snowflakes form, which precipitate when they reach a critical mass.
The average residence time of water molecules in the troposphere is about 10 days. Water depleted by precipitation is replenished by evaporation from the seas, lakes, rivers and the transpiration of plants, and other biological and geological processes.
Measurements of vapor concentration are expressed as specific humidity or percent relative humidity. The annual mean global concentration of water vapor would yield about 25 mm of liquid water over the entire surface of the Earth if it were to instantly condense. However, the mean annual precipitation for the planet is about 1 meter, which indicates a rapid turnover of water in the air.
The abundance of gases emitted by volcanoes varies considerably from volcano to volcano. However, water vapor is consistently the most common volcanic gas, normally comprising more than 60% of total emissions during a subaerial volcanic eruption.[11]
## Radar and satellite imaging
Because water molecules absorb microwaves and other radio wave frequencies, water in the atmosphere attenuates radar signals.[12] In addition, atmospheric water will reflect and refract signals to an extent that depends on whether it is vapor, liquid or solid.[13]
Generally, radar signals lose strength progressively the farther they travel through the troposphere. Different frequencies attenuate at different rates, such that some components of air are opaque to some frequencies and transparent to others. Radio waves used for broadcasting and other communication experience the same effect.
Water vapor reflects radar[14] to a less extent than do water's other two phases. In the form of drops and ice crystals, water acts as a prism, which it does not do as an individual molecule; however, the existence of water vapor in the atmosphere causes the atmosphere to act as a giant prism.[15]
A comparison of GOES-12 satellite images shows the distribution of atmospheric water vapor relative to the oceans, clouds and continents of the Earth. Vapor surrounds the planet but is unevenly distributed.
## Lightning generation
Water vapor plays a key role in lightning production in the atmosphere. From cloud physics, usually, clouds are the real generators of static charge as found in Earth's atmosphere. But the ability, or caterbility of clouds to hold massive amounts of electrical energy is directly related to the amount of water vapor present in the local system.
The amount of water vapor directly controls the permittivity of the air. During times of low humidity, static discharge is quick and easy. During times of higher humidity, fewer static discharges occur. However, permittivity and capacitance[16] work hand in hand to produce the megawatt outputs of lightning.
After a cloud, for instance, has started its way to becoming a lightning generator, atmospheric water vapor acts as a substance (or insulator[17] [18] ) that decreases the ability of the cloud to discharge its electrical energy. Over a certain amount of time, if the cloud continues to generate and store[19] more static electricity[20], the barrier that was created by the atmospheric water vapor will ultimately break down[21] from the stored electrical potential energy. This energy will be released to a locally, opposite[22] charged region in the form of lightning. The strength of each discharge is directly related to the atmospheric permittivity, capacitance, and the source's charge generating ability.[23]
See also, Van de Graaff generator.
## Extraterrestrial water vapor
The brilliance of comet tails comes largely from water vapor. On approach to the sun, the ice many comets carry sublimates to vapor, which reflects light from the sun. Knowing a comet's distance from the sun, astronomers may deduce a comet's water content from its brilliance.[24] Bright tails in cold and distant comets suggests carbon monoxide sublimation.
Scientists studying Mars hypothesize that if water moves about the planet, it does so as vapor.[25] Most of the water on Mars appears to exist as ice at the northern pole. During Mars' summer, this ice sublimates, perhaps enabling massive seasonal storms to convey significant amounts of water toward the equator.[26]
A star called CW Leonis was found to have a ring of vast quantities of water vapor circling the aging, massive star. A NASA satellite designed to study chemicals in interstellar gas clouds, made the discovery with an onboard spectrometer. Most likely, "the water vapor was vaporized from the surfaces of orbiting comets."[27]
Spectroscopic analysis of HD 209458 b, an extrasolar planet in the constellation Pegasus, provides the first evidence of atmospheric water vapor beyond the Solar System.
# Scientific Discrepancies, Confounding factors and limits of knowledge
Since water vapor is very common, it has been studied and written about from many perspectives. As a working knowledge has grown and developed within apparently unrelated fields several discrepancies in understanding may be encountered. These discrepancies often arise from an inability to rigidly determine either a Volumetric or Gravimetric basis of study ; and/or use of constants inappropriate for the conditions being observed.
Many scientific studies view water vapor as a Confounding variable (preventing Ceteris paribus, also 'lurking varible') due to its complex nature, this becomes especially true when the study observes significant variation in water vapor quantities, over time and/or location.
It is for the reasons above that this remains a particularly tricky and sometimes controversial factor in many fields of science, whether storage of foods or ancient artefacts, Thermodynamics or Climate Change. | https://www.wikidoc.org/index.php/Water_vapor | |
d3cdc5074990a9a8d05b8ae28338ae9b8977fd1e | wikidoc | White guilt | White guilt
"White guilt" refers to a controversial concept of individual or collective guilt often said to be felt by some white people for the racist treatment of people of color by whites both historically and presently. The term is generally used in pejorative way, usually by those who criticize efforts to assist non-whites, particularly with policies or decisions the critics believe give advantages or benefits to them unfair to whites. Many on the left have rejected the idea that guilt is the motivating factor for these efforts.
The term is often applied to white Americans regarding the history of enslavement of African Americans, and colonization and displacement of Native Americans and Native Hawaiians. In addition, white guilt may be experienced by citizens of European countries whose nations participated in the slave trade and/or colonized portions of Asia and South Asia, Africa and North Africa, the Middle East, and the Americas. White guilt has been described as one of several psychosocial costs of racism for White individuals along with the ability to have empathic reactions towards racism, and fear of non-whites.
According to Shelby Steele, white guilt is "a form of self-congratulation, where whites initiate "compassionate policies" toward people of color, to showcase their innocance to racism. Steele has put the term in the context of American history and society in his book White Guilt: How Blacks and Whites Together Destroyed the Promise of the Civil Rights Era (2006):
"White guilt" may be used as a political epithet in an attempt to discredit or misrepresent anti-racist thought and practice.
# Criticism of the concept
Criticism of the idea that white guilt animates most whites or most whites on the left is common from left-wing or American liberal commentators. Sunny Hundal, writing in The Guardian in September 2007, asserted that "Not much annoys me more than the stereotype that to be liberal is to be full of guilt. To be socially liberal, in my view, is to be more mindful of compassion and empathy for others." Hundal wrote that motivations for political opinions that are based on collective guilt create a "reductionist", simplistic view of the world that few people on the left actually share.
# Use of the concept outside of politics
Judith Katz author of White Awareness: Handbook for Anti-Racism Training is highly critical of what she calls self-indulgent white guilt fixations. Her concerns about white guilt led her to move from black-white group encounters to all-white groups in her anti-racism training. She also avoided using people of color to reeducate whites, she said, because she found that this led whites to focus on getting acceptance and forgiveness rather than changing their own actions or beliefs. Statements about racial inequality may be framed as either White privileges or Black disadvantages, when framed as White privileges a 2005 study found that the statements resulted in greater collective guilt and lower racism compared to a Black disadvantage framing. The findings suggest that representing inequality in terms of outgroup disadvantage allows privileged group members to avoid the negative psychological implications of inequality and supports prejudicial attitudes.
Con artists have been accused of using white guilt: "Telephone and mail solicitors, trading on "white guilt" and on government pressure to advertise in minority-oriented publications, are inducing thousands of businessmen to buy ads in phony publications", according to a 1978 Washington Post article. | White guilt
"White guilt" refers to a controversial concept of individual or collective guilt often said to be felt by some white people for the racist treatment of people of color by whites both historically and presently.[1] The term is generally used in pejorative way, usually by those who criticize efforts to assist non-whites, particularly with policies or decisions the critics believe give advantages or benefits to them unfair to whites. Many on the left have rejected the idea that guilt is the motivating factor for these efforts.
The term is often applied to white Americans regarding the history of enslavement of African Americans, and colonization and displacement of Native Americans and Native Hawaiians. In addition, white guilt may be experienced by citizens of European countries whose nations participated in the slave trade and/or colonized portions of Asia and South Asia, Africa and North Africa, the Middle East, and the Americas. White guilt has been described as one of several psychosocial costs of racism for White individuals along with the ability to have empathic reactions towards racism, and fear of non-whites.[2]
According to Shelby Steele, white guilt is "a form of self-congratulation, where whites initiate "compassionate policies" toward people of color, to showcase their innocance to racism.[3] Steele has put the term in the context of American history and society in his book White Guilt: How Blacks and Whites Together Destroyed the Promise of the Civil Rights Era (2006):
"White guilt" may be used as a political epithet in an attempt to discredit or misrepresent anti-racist thought and practice.[citation needed]
# Criticism of the concept
Criticism of the idea that white guilt animates most whites or most whites on the left is common from left-wing or American liberal commentators. Sunny Hundal, writing in The Guardian in September 2007, asserted that "Not much annoys me more than the stereotype that to be liberal is to be full of guilt. To be socially liberal, in my view, is to be more mindful of compassion and empathy for others." Hundal wrote that motivations for political opinions that are based on collective guilt create a "reductionist", simplistic view of the world that few people on the left actually share.[5]
# Use of the concept outside of politics
Judith Katz author of White Awareness: Handbook for Anti-Racism Training is highly critical of what she calls self-indulgent white guilt fixations. Her concerns about white guilt led her to move from black-white group encounters to all-white groups in her anti-racism training. She also avoided using people of color to reeducate whites, she said, because she found that this led whites to focus on getting acceptance and forgiveness rather than changing their own actions or beliefs.[6] Statements about racial inequality may be framed as either White privileges or Black disadvantages, when framed as White privileges a 2005 study found that the statements resulted in greater collective guilt and lower racism compared to a Black disadvantage framing. The findings suggest that representing inequality in terms of outgroup disadvantage allows privileged group members to avoid the negative psychological implications of inequality and supports prejudicial attitudes.[7]
Con artists have been accused of using white guilt: "Telephone and mail solicitors, trading on "white guilt" and on government pressure to advertise in minority-oriented publications, are inducing thousands of businessmen to buy ads in phony publications", according to a 1978 Washington Post article.[8] | https://www.wikidoc.org/index.php/White_guilt | |
fdf288a29ed996b057a20c0d26757183f7e07107 | wikidoc | Wild carrot | Wild carrot
Wild carrot, bishop's lace, or queen anne's lace (Daucus carota) is a flowering plant in the family Apiaceae, native to temperate regions of Europe and southwest Asia; domesticated carrots are cultivars of a subspecies, Daucus carota subsp. sativus.
Daucus carota is a variable biennial plant, usually growing up to 1 m tall and flowering from June to August. The umbels are claret-coloured or pale pink before they open, then bright white and rounded when in full flower, measuring 3-7cm wide with a festoon of bracts beneath; finally, as they turn to seed, they contract and become concave like a bird's nest. This has given the plant its British common or vernacular name, Bird's Nest. Very similar in appearance to the deadly poison hemlock, it is distinguished by a mix of bi-pinnate and tri-pinnate leaves, fine hairs on its stems and leaves, a root that smells like carrots, and occasionally a single dark red flower in its center.
# Cultivation and uses
See carrot for the modern cultivated forms of the species.
Like the cultivated carrot, the wild carrot root is edible while young, but quickly becomes too woody to consume. A teaspoon of crushed seeds has long been used as a form of natural birth control – its use for this purpose was first described by Hippocrates over 2,000 years ago. Research conducted on mice has offered a degree of confirmation for this use – it was found that wild carrot disrupts the implantation process, which reinforces its reputation as a contraceptive. Chinese studies have also indicated that the seeds block progesterone synthesis, which could explain this effect.
It is recommended that, as with all herbal remedies and wild food gathering, one should use appropriate caution. Extra caution should be used in this case, as it bears close resemblance to a dangerous species (see Water Hemlock). The leaves of the wild carrot can be a skin irritant, so caution should also be used when handling the plant.
# Queen Anne's lace
Wild carrot was introduced and naturalised in North America, where it is often known as "Queen Anne's lace". It is so called because the flower resembles lace; the red flower in the center represents a blood droplet where Queen Anne pricked herself with a needle when she was making the lace. The function of the tiny red flower, coloured by anthocyanin, is to attract insects.
The USDA has listed it as a noxious weed , and it is considered a serious pest in pastures.
- A young Queen Anne's Lace with red flower in center.
A young Queen Anne's Lace with red flower in center.
- Queen Anne's Lace in southern Maine.
Queen Anne's Lace in southern Maine.
- Queen Anne's Lace on Prince Edward Island.
Queen Anne's Lace on Prince Edward Island. | Wild carrot
Wild carrot, bishop's lace, or queen anne's lace (Daucus carota) is a flowering plant in the family Apiaceae, native to temperate regions of Europe and southwest Asia; domesticated carrots are cultivars of a subspecies, Daucus carota subsp. sativus.
Daucus carota is a variable biennial plant, usually growing up to 1 m tall and flowering from June to August. The umbels are claret-coloured or pale pink before they open, then bright white and rounded when in full flower, measuring 3-7cm wide with a festoon of bracts beneath; finally, as they turn to seed, they contract and become concave like a bird's nest. This has given the plant its British common or vernacular name, Bird's Nest. Very similar in appearance to the deadly poison hemlock, it is distinguished by a mix of bi-pinnate and tri-pinnate leaves, fine hairs on its stems and leaves, a root that smells like carrots, and occasionally a single dark red flower in its center.
# Cultivation and uses
See carrot for the modern cultivated forms of the species.
Like the cultivated carrot, the wild carrot root is edible while young, but quickly becomes too woody to consume. A teaspoon of crushed seeds has long been used as a form of natural birth control – its use for this purpose was first described by Hippocrates over 2,000 years ago. Research conducted on mice has offered a degree of confirmation for this use – it was found that wild carrot disrupts the implantation process, which reinforces its reputation as a contraceptive. Chinese studies have also indicated that the seeds block progesterone synthesis, which could explain this effect.
It is recommended that, as with all herbal remedies and wild food gathering, one should use appropriate caution. Extra caution should be used in this case, as it bears close resemblance to a dangerous species (see Water Hemlock). The leaves of the wild carrot can be a skin irritant, so caution should also be used when handling the plant.
# Queen Anne's lace
Wild carrot was introduced and naturalised in North America, where it is often known as "Queen Anne's lace". It is so called because the flower resembles lace; the red flower in the center represents a blood droplet where Queen Anne pricked herself with a needle when she was making the lace. The function of the tiny red flower, coloured by anthocyanin, is to attract insects.
The USDA has listed it as a noxious weed [1], and it is considered a serious pest in pastures.
- A young Queen Anne's Lace with red flower in center.
A young Queen Anne's Lace with red flower in center.
- Queen Anne's Lace in southern Maine.
Queen Anne's Lace in southern Maine.
- Queen Anne's Lace on Prince Edward Island.
Queen Anne's Lace on Prince Edward Island. | https://www.wikidoc.org/index.php/Wild_carrot | |
4aa616947e032f2deac5e80c86acc428a74ddd7f | wikidoc | Wild ginger | Wild ginger
Wild ginger refers to an herbaceous plant genus Asarum (Á-sa-rum) of the birthwort family Aristolochiaceae.
Asarum canadense is native to the forests of eastern North America. It is found from the Great Plains east to the Atlantic Coast, and from southeastern Canada south to approximately the fall line in the southeastern United States.
Asarum caudatum is found in British Columbia south through Washington and Oregon to central California, and from the Coast Range east to western Montana.
The plant is called wild ginger because the rhizome tastes and smells similar to that of ginger root, but the two are not particularly related. The root can be used as a spice, but is a potent diuretic, or urinary stimulant. Asarum canadense and other species in the genus contain the chemical aristolochic acid, which is carcinogenic in rats. The birthwort family also contains the Aristolochia genus. Aristolochia is a human carcinogen.
Wild ginger favors moist, shaded sites with humus-rich soil. The deciduous, heart-shaped leaves are opposite, and borne from the rhizome which lies just under the soil surface. Two leaves emerge each year from the growing tip. The curious jug-shaped flowers, which give the plant an alternate name, little jug, are borne singly in Spring between the leaf bases.
Wild ginger can easily be grown in a shade garden, and makes an attractive groundcover.
# Species
- Asarum arifolium
- Asarum canadense : Wild Ginger, Black Snakeroot, Canada Wild Ginger, Canadian Snakeroot, Broad-leaved Asarabacca.
- Asarum caudatum : Long-tailed Wild ginger
Asarum caudatum caudatum : British Columbia Wild ginger.
Asarum caudatum viridiflorum : Longtail Wild Ginger).
- Asarum caudatum caudatum : British Columbia Wild ginger.
- Asarum caudatum viridiflorum : Longtail Wild Ginger).
- Asarum europaeum : Asarabacca, European Wild Ginger, Haselwort, Wild Spikenard.
- Asarum hartwegii : Hartweg's Wild Ginger.
- Asarum hongkongensis : Hong Kong Wild Ginger.
- Asarum lemmonii : Lemmon's Wild Ginger.
- Asarum marmoratum : Marbled Wild Ginger.
- Asarum naniflorum
- Asarum splendens: Chinese Wild Ginger. | Wild ginger
Wild ginger refers to an herbaceous plant genus Asarum (Á-sa-rum) of the birthwort family Aristolochiaceae.
Asarum canadense is native to the forests of eastern North America. It is found from the Great Plains east to the Atlantic Coast, and from southeastern Canada south to approximately the fall line in the southeastern United States.
Asarum caudatum is found in British Columbia south through Washington and Oregon to central California, and from the Coast Range east to western Montana.
The plant is called wild ginger because the rhizome tastes and smells similar to that of ginger root, but the two are not particularly related. The root can be used as a spice, but is a potent diuretic, or urinary stimulant. Asarum canadense and other species in the genus contain the chemical aristolochic acid, which is carcinogenic in rats. The birthwort family also contains the Aristolochia genus. Aristolochia is a human carcinogen.
Wild ginger favors moist, shaded sites with humus-rich soil. The deciduous, heart-shaped leaves are opposite, and borne from the rhizome which lies just under the soil surface. Two leaves emerge each year from the growing tip. The curious jug-shaped flowers, which give the plant an alternate name, little jug, are borne singly in Spring between the leaf bases.
Wild ginger can easily be grown in a shade garden, and makes an attractive groundcover.
# Species
- Asarum arifolium
- Asarum canadense : Wild Ginger, Black Snakeroot, Canada Wild Ginger, Canadian Snakeroot, Broad-leaved Asarabacca.
- Asarum caudatum : Long-tailed Wild ginger
Asarum caudatum caudatum : British Columbia Wild ginger.
Asarum caudatum viridiflorum : Longtail Wild Ginger).
- Asarum caudatum caudatum : British Columbia Wild ginger.
- Asarum caudatum viridiflorum : Longtail Wild Ginger).
- Asarum europaeum : Asarabacca, European Wild Ginger, Haselwort, Wild Spikenard.
- Asarum hartwegii : Hartweg's Wild Ginger.
- Asarum hongkongensis : Hong Kong Wild Ginger.
- Asarum lemmonii : Lemmon's Wild Ginger.
- Asarum marmoratum : Marbled Wild Ginger.
- Asarum naniflorum
- Asarum splendens: Chinese Wild Ginger. | https://www.wikidoc.org/index.php/Wild_ginger | |
877204d23d25b5ec8e0f84bc95e5846ae2a4afdb | wikidoc | Witch-hazel | Witch-hazel
Witch-hazel (Hamamelis) is a genus of four species of flowering plants in the family Hamamelidaceae, with two species in North America (H. virginiana and H. vernalis), and one each in Japan (H. japonica) and China (H. mollis).
They are deciduous shrubs or (rarely) small trees growing to 3-8 m tall, rarely to 12 m tall. The leaves are alternately arranged, oval, 4-16 cm long and 3-11 cm broad, with a smooth or wavy margin. The horticultural name means "together with fruit"; its fruit, flowers, and next year's leaf buds all appear on the branch simultaneously, a rarity among trees. The flowers are produced on the leafless stems in winter, thus one alternative name for the plant, "Winterbloom". Each flower has four slender strap-shaped petals 1-2 cm long, pale to dark yellow, orange, or red. The fruit is a two-part capsule 1 cm long, containing a single 5 mm glossy black seed in each of the two parts; the capsule splits explosively at maturity in the autumn about 8 months after flowering, ejecting the seeds with sufficient force to fly for distances of up to 10 m, thus another alternative name "Snapping Hazel".
Hamamelis species are used as food plants by the larvae of some Lepidoptera species including Feathered Thorn.
The name Witch has its origins in Middle English wiche, from the Old English wice, meaning "pliant" or "bendable". Hazel is derived from the use of the twigs as divining rods, just as hazel twigs were used in England.
The Persian Ironwood, a closely related tree formerly treated as Hamamelis persica, is now given a genus of its own, as Parrotia persica, as it differs in the flowers not having petals. Other closely allied genera are Parrotiopsis, Fothergilla and Sycopsis (see under Hamamelidaceae). Witch-hazels are not closely related to the hazels.
# Cultivation and uses
They are popular ornamental plants, grown for their clusters of rich yellow to orange-red flowers which begin to expand in the autumn as or slightly before the leaves fall, and continue throughout the winter. Numerous cultivars have been selected for use as garden shrubs, many of them derived from the hybrid H. × intermedia Rehder (H. japonica × H. mollis).
The bark and leaves are astringent; the extract, also referred to as witch hazel, is used medicinally. Extracts from its bark and leaves are used in aftershave lotions and lotions for treating bruises and insect bites. Witch-hazel is the active ingredient in many hemorrhoid medications. The seeds contain a quantity of oil and are edible. | Witch-hazel
Witch-hazel (Hamamelis) is a genus of four species of flowering plants in the family Hamamelidaceae, with two species in North America (H. virginiana and H. vernalis), and one each in Japan (H. japonica) and China (H. mollis).
They are deciduous shrubs or (rarely) small trees growing to 3-8 m tall, rarely to 12 m tall. The leaves are alternately arranged, oval, 4-16 cm long and 3-11 cm broad, with a smooth or wavy margin. The horticultural name means "together with fruit"; its fruit, flowers, and next year's leaf buds all appear on the branch simultaneously, a rarity among trees. [1] The flowers are produced on the leafless stems in winter, thus one alternative name for the plant, "Winterbloom". [1] Each flower has four slender strap-shaped petals 1-2 cm long, pale to dark yellow, orange, or red. The fruit is a two-part capsule 1 cm long, containing a single 5 mm glossy black seed in each of the two parts; the capsule splits explosively at maturity in the autumn about 8 months after flowering, ejecting the seeds with sufficient force to fly for distances of up to 10 m, thus another alternative name "Snapping Hazel". [1]
Hamamelis species are used as food plants by the larvae of some Lepidoptera species including Feathered Thorn.
The name Witch has its origins in Middle English wiche, from the Old English wice, meaning "pliant" or "bendable". Hazel is derived from the use of the twigs as divining rods, just as hazel twigs were used in England.
The Persian Ironwood, a closely related tree formerly treated as Hamamelis persica, is now given a genus of its own, as Parrotia persica, as it differs in the flowers not having petals. Other closely allied genera are Parrotiopsis, Fothergilla and Sycopsis (see under Hamamelidaceae). Witch-hazels are not closely related to the hazels.
## Cultivation and uses
They are popular ornamental plants, grown for their clusters of rich yellow to orange-red flowers which begin to expand in the autumn as or slightly before the leaves fall, and continue throughout the winter. Numerous cultivars have been selected for use as garden shrubs, many of them derived from the hybrid H. × intermedia Rehder (H. japonica × H. mollis).
The bark and leaves are astringent; the extract, also referred to as witch hazel, is used medicinally. Extracts from its bark and leaves are used in aftershave lotions and lotions for treating bruises and insect bites. Witch-hazel is the active ingredient in many hemorrhoid medications. The seeds contain a quantity of oil and are edible. | https://www.wikidoc.org/index.php/Witch-hazel | |
ee96b2057b66cda2e8a9bdd024424b26f2238fd9 | wikidoc | Xanthelasma | Xanthelasma
Synonyms and keywords:: Xanthelasma palpebrarum.
# Overview
Xanthelasma (or xanthelasma palpebrarum) is a sharply demarcated yellowish collection of cholesterol underneath the skin, usually on or around the eyelids. The plural is "xanthelasmata". The root of the word is from Greek xanthos, ξανθος, "yellow".
Xanthelasma are distinct from xanthoma which are larger and nodular, lesions. Xanthelasma are sometimes classified as a subtype of xanthoma.
# Epidemiology and Demographics
A study of 12,745 people from Denmark identified xanthelasmata in 4.4% of participants aged 20-93.
# Natural History, Complications, Prognosis
The lesions themselves are not harmful or painful. They may, however, be a marker of underlying atherosclerosis.
## Association with Atherosclerosis
In a prospective population based cohort study (The Copenhagen City Heart Study), a total of 12,745 participants who were free of ischemic heart disease and aged 20-93 years were followed for a mean of 22 years . The mulivariate adjusted risk (hazard/odds ratios adjusted for confounders including cholesterol and triglyceride concentrations) of an adverse outcome associated with the presence of xanthelasmata were as follows:
- Myocardial infarction: 1.48 (95% confidence interval 1.23 to 1.79)
- Ischemic stroke: 0.94 (0.73 to 1.21)
- Death: 1.14 (1.04 to 1.26) for death.
Thus, independent of other cardiac risk factors, the presence of a xanthelasma appers to be an independent risk factor for atherosclerotic heart disease. In the same study, arcus senilis was not identified as an independent risk factor.
## Gallery
### Head
- url = >
- url = >
- url = >
### Extremities
- url = >
### Trunk
- url = >
# Differential Diagnosis of Associated Conditions
- Diabetes
- High cholesterol levels (specifically familial hypercholesterolemia)
- LDL receptor deficiency
- Menopause
- Primary biliary cirrhosis
- Vitamin E deficiency (familial isolated, autosomal recessive inheritance)
# Treatment
These minor growths may be disfiguring and can be removed. Xanthelasmata can be removed with trichloroacetic acid peel, surgery, lasers or cryotherapy. Removal can cause scarring and pigment changes, but it is unusual after treatment with trichloroacetic acid. | Xanthelasma
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
Synonyms and keywords:: Xanthelasma palpebrarum.
# Overview
Xanthelasma (or xanthelasma palpebrarum) is a sharply demarcated yellowish collection of cholesterol underneath the skin, usually on or around the eyelids. The plural is "xanthelasmata". The root of the word is from Greek xanthos, ξανθος, "yellow".
Xanthelasma are distinct from xanthoma which are larger and nodular, lesions.[1] Xanthelasma are sometimes classified as a subtype of xanthoma.[2]
# Epidemiology and Demographics
A study of 12,745 people from Denmark identified xanthelasmata in 4.4% of participants aged 20-93.
# Natural History, Complications, Prognosis
The lesions themselves are not harmful or painful. They may, however, be a marker of underlying atherosclerosis[3].
## Association with Atherosclerosis
In a prospective population based cohort study (The Copenhagen City Heart Study), a total of 12,745 participants who were free of ischemic heart disease and aged 20-93 years were followed for a mean of 22 years [4]. The mulivariate adjusted risk (hazard/odds ratios adjusted for confounders including cholesterol and triglyceride concentrations) of an adverse outcome associated with the presence of xanthelasmata were as follows:
- Myocardial infarction: 1.48 (95% confidence interval 1.23 to 1.79)
- Ischemic stroke: 0.94 (0.73 to 1.21)
- Death: 1.14 (1.04 to 1.26) for death.
Thus, independent of other cardiac risk factors, the presence of a xanthelasma appers to be an independent risk factor for atherosclerotic heart disease. In the same study, arcus senilis was not identified as an independent risk factor[5].
## Gallery
### Head
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=500>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=500>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=500>
### Extremities
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=500>
### Trunk
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=500>
# Differential Diagnosis of Associated Conditions
- Diabetes
- High cholesterol levels (specifically familial hypercholesterolemia)
- LDL receptor deficiency
- Menopause
- Primary biliary cirrhosis
- Vitamin E deficiency (familial isolated, autosomal recessive inheritance)
# Treatment
These minor growths may be disfiguring and can be removed. Xanthelasmata can be removed with trichloroacetic acid peel, surgery, lasers or cryotherapy. Removal can cause scarring and pigment changes, but it is unusual after treatment with trichloroacetic acid. | https://www.wikidoc.org/index.php/Xanthelasma | |
9628850ea0cf82bf4206e3da5eebd29070e27212 | wikidoc | Xanthinuria | Xanthinuria
# Overview
Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase.
It was first formally characterized in 1954.
# Causes
It can be caused by a deficiency of xanthine oxidase, which is an enzyme necessary for converting xanthine to uric acid.
# Presentation
Sufferers have unusually high concentrations of xanthine in their blood and urine, which can lead to health problems such as renal failure and xanthine kidney stones, one of the rarest types of kidney stones.
# Treatment
There is no specific treatment beyond maintaining a high fluid intake and avoiding foods that are high in purine. | Xanthinuria
Template:DiseaseDisorder infobox
# Overview
Xanthinuria, also known as xanthine oxidase deficiency, is a rare genetic disorder causing the accumulation of xanthine. It is caused by a deficiency of the enzyme xanthine oxidase.
It was first formally characterized in 1954.[1]
# Causes
It can be caused by a deficiency of xanthine oxidase, which is an enzyme necessary for converting xanthine to uric acid. [2]
# Presentation
Sufferers have unusually high concentrations of xanthine in their blood and urine, which can lead to health problems such as renal failure and xanthine kidney stones, one of the rarest types of kidney stones.
# Treatment
There is no specific treatment beyond maintaining a high fluid intake and avoiding foods that are high in purine. | https://www.wikidoc.org/index.php/Xanthine_oxidase_deficiency | |
8194a364ff2f1075e49efbb16bb4be8bc222ab39 | wikidoc | Zen Shiatsu | Zen Shiatsu
Zen Shiatsu is a derivative form of the Japanese therapy Shiatsu, and is particularly popular in the United Kingdom and United States. It was developed by Shizuto Masunaga, a graduate of the Japan Shiatsu College who published a book entitled Shiatsu in 1974. This was translated into English in 1977 and retitled Zen Shiatsu. The name "Zen Shiatsu" was not coined by Masunaga himself but by Wataru Ohashi, the co-author of the English version.
Zen Shiatsu, also known as Masunaga Therapy, is a form of Meridian Shiatsu. A difference between Masunaga's Zen Shiatsu and earlier forms of Shiatsu is that Zen Shiatsu uses not only thumbs and palms but also fists, elbows, and knees.
Zen Shiatsu represents a return of the values of Traditional Chinese medicine, in comparison with anatomically or physiologically based Shiatsu (cf. Tsubo Shiatsu). While the Namikoshi school emphasizes Westernization at the expense of Chinese medical understanding, Masunaga advocated a return to Chinese Taoist practices such as Do-In and Ankyo within the context of Japanese Shiatsu.
The meridian system represents the "crosstalk" between tsubos or acupoints of the human body. It also represents divisions of the complete function of the human organism into discrete spheres of influence. Masunaga advocated treating the whole meridian system through pressure and stretching to achieve systemic change for the entire body.
Shizuto Masunaga founded a Japanese institute called the Iokai Center. "Io" means king/master of medicine, and "kai" means group/association. This center continues to the present day, propagating Masunaga's methods. Zen Shiatsu has proven to be widely influential throughout the US and UK. Students of Masunaga include Wataru Ohashi, Pauline Sasaki, Ryokyu Endo and Stephen Brown.
The primary precept of Zen Shiatsu is the importance of remaining in a Zen-like, present state when practicing shiatsu; nourishing weak kyo areas and dispersing excess jitsu areas; using two-handed technique to better feel the flow of qi (life force); working from the hara (belly), which is the body's energy center; and using perpendicular pressure to access the qi. Masunaga moreover expanded the meridian system, discovering extensions of the classical Chinese meridians, and developed an effective new system of hara diagnosis predicated on his experience as a Western-trained psychologist. | Zen Shiatsu
Zen Shiatsu is a derivative form of the Japanese therapy Shiatsu, and is particularly popular in the United Kingdom and United States. It was developed by Shizuto Masunaga, a graduate of the Japan Shiatsu College who published a book entitled Shiatsu in 1974. This was translated into English in 1977 and retitled Zen Shiatsu. The name "Zen Shiatsu" was not coined by Masunaga himself but by Wataru Ohashi, the co-author of the English version.
Zen Shiatsu, also known as Masunaga Therapy, is a form of Meridian Shiatsu. A difference between Masunaga's Zen Shiatsu and earlier forms of Shiatsu is that Zen Shiatsu uses not only thumbs and palms but also fists, elbows, and knees.
Zen Shiatsu represents a return of the values of Traditional Chinese medicine, in comparison with anatomically or physiologically based Shiatsu (cf. Tsubo Shiatsu). While the Namikoshi school emphasizes Westernization at the expense of Chinese medical understanding, Masunaga advocated a return to Chinese Taoist practices such as Do-In and Ankyo within the context of Japanese Shiatsu.
The meridian system represents the "crosstalk" between tsubos or acupoints of the human body. It also represents divisions of the complete function of the human organism into discrete spheres of influence. Masunaga advocated treating the whole meridian system through pressure and stretching to achieve systemic change for the entire body.
Shizuto Masunaga founded a Japanese institute called the Iokai Center. "Io" means king/master of medicine, and "kai" means group/association. This center continues to the present day, propagating Masunaga's methods. Zen Shiatsu has proven to be widely influential throughout the US and UK. Students of Masunaga include Wataru Ohashi, Pauline Sasaki, Ryokyu Endo and Stephen Brown.
The primary precept of Zen Shiatsu is the importance of remaining in a Zen-like, present state when practicing shiatsu; nourishing weak kyo areas and dispersing excess jitsu areas; using two-handed technique to better feel the flow of qi (life force); working from the hara (belly), which is the body's energy center; and using perpendicular pressure to access the qi. Masunaga moreover expanded the meridian system, discovering extensions of the classical Chinese meridians, and developed an effective new system of hara diagnosis predicated on his experience as a Western-trained psychologist.
# External Links
- Zen Shiatsu Chicago - Illinois Shiatsu School, Member of AOBTA Council of Schools
- AOBTA American Organization for Bodywork Therapies of Asia
- [http://www.yogawelt.com Zen Shiatsu Meridian resource
- [http://www.shiatsu-sgs.ch Shiatsu Society (Gesellschaft) Switzerland
- Australian Shiatsu College
- Southern School of Natural Therapies Australia
- [http://www.shiatsutherapy.ca Shiatsu Therapy Association of British Columbia
- More about Zen Shiatsu (Bilingual Site)
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Zen_Shiatsu | |
2072422b09765d8fe10d5315afb7608ac837a217 | wikidoc | Zinc iodide | Zinc iodide
Zinc iodide is composed of Zinc and Iodine. It is an inorganic compound with a molecular weight of 319.22. It is a white, granular, odorless solid that absorbs water from the atmosphere and then dissolves into a solution. At 1150°C, zinc iodide vapor dissociates into zinc and iodine.
Zinc iodide is often used as an x-ray opaque penetrant in industrial radiography to improve the contrast between the damage and intact composite.
United States Patent 4109065 describes a rechargeable aqueous zinc-halogen cell which includes an aqueous electrolytic solution containing a zinc salt selected from the class consisting of zinc bromide, zinc iodide, and mixtures thereof, in both positive and negative electrode compartments. | Zinc iodide
Template:Cleanup
Zinc iodide is composed of Zinc and Iodine. It is an inorganic compound with a molecular weight of 319.22. It is a white, granular, odorless solid that absorbs water from the atmosphere and then dissolves into a solution. At 1150°C, zinc iodide vapor dissociates into zinc and iodine.
Zinc iodide is often used as an x-ray opaque penetrant in industrial radiography to improve the contrast between the damage and intact composite.
United States Patent 4109065 describes a rechargeable aqueous zinc-halogen cell which includes an aqueous electrolytic solution containing a zinc salt selected from the class consisting of zinc bromide, zinc iodide, and mixtures thereof, in both positive and negative electrode compartments. | https://www.wikidoc.org/index.php/Zinc_iodide | |
7814a499451242b0d34a393b6491e1b79a1c9ce2 | wikidoc | 2-Pyridone | 2-Pyridone
2-Pyridone is the chemical compound with the formula C5H4NH(O). This colourless crystalline solid is used in peptide synthesis. It is well known to form hydrogen bonded structures somewhat related to the base-pairing mechanism found in RNA and DNA. It is also a classic case of a molecule that exists as tautomers.
# Structure
The most prominent feature of the 2-pyridone is the amide group, a nitrogen with a hydrogen bound to it and a keto group next to it. In peptides, amino acids are linked by this pattern.
This pattern is responsible for some remarkable physical and chemical properties.
The hydrogen bound to the nitrogen is suitable to form strong hydrogen bonds to other nitrogen- and oxygen-containing species.
# Tautomerism
The hydrogen bond to the nitrogen is also suitable to move to the oxygen. Through hydrogen and electron shift the second tautomer form of the substance is formed. 2-hydroxypyridine is the name for this tautomer. This lactam lactim tautomerism can also be found in other molecules with a similar structure.
## Tautomerism in Solid State
The predominant form in solid state is the 2-pyridone. This fact has been clarified by X-ray crystallography which shows that the hydrogen in solid state is closer to the nitrogen than to the oxygen (because of the low electron density at the hydrogen the exact positioning is difficult) and IR-spectroscopy in which the C=O longitudinal frequency is present and the O-H frequencies are absent.
## Tautomerism in Solution
To determine which of the two tautomeric forms is present in solution has been the subject of many publications. The energy difference seems to be very small and depending on the polarity of the solvent. Nonpolar solvents favour the 2-hydroxypyridine whereas in polar solvents like alcohols and water the 2-pyridone is favoured.
The energy difference for the two tautomers in the gas phase was measured by IR-spectroscopy to be 2.43 to 3.3 kJ/mol for the solid state and 8.95 kJ/mol and 8.83 kJ/mol for the liquid state.
## Tautomerisation Mechanism A
The single molecular tautomerisation has a forbidden 1-3 suprafacial transition state and therefore has a high energy barrier for this tautomerisation, which was calculated with theoretical methods to be 125 or 210 kJ/mol. The direct tautomerisation is energetically not favoured. There are other possible mechanisms for this tautomerisation.
# Dimerisation
dimer
The 2-pyridone and the 2-hydroxypyridine can form dimers with two hydrogen bonds.
## Aggregation in Solid-state
In solid state the dimeric form is not present; the 2-pyridones form a helical structure over hydrogen bonds. Some substituted 2-pyridones form the dimer in solid state, for example the 5-methyl-3-carbonitrile-2-pyridone. The determination of all these structures was done by X-ray crystallography.
In solid state the hydrogen is located closer to the oxygen so it could be considered to be right to call the colourless crystals in the flask 2-pyridone.
## Aggregation in Solution
In solution the dimeric form is present; the ratio of dimerisation is strongly dependent on the polarity of the solvent. Polar and protic solvents interact with the hydrogen bonds and more monomer is formed. hydrophobic effects in unpolar solvents lead to a predominance of the dimere. Also the ratio of the tautomeric forms is dependent on the solvent. All possible tautomers and dimmers can be present and form an equilibrium. The exact measurement of all the equilibrium constants in the system are extremely difficult.
(NMR-spectroscopy is a slow method, high resolution IR-spectroscopy in solvent is difficult, the broad absorption in UV-spectroscopy makes it hard to discriminate 3 and more very similar molecules).
Some publications only focus one of the two possible patterns, and neglect the influence of the other. For example to calculate the energy difference of the two tautomeres in nonpolar solution, leads too a wrong results if a large quantity of the substance is on the side of the dimer in an equilibrium.
## Tautomerisation Mechanism B
The direct tautomerisation is energetically not favoured, but a dimerisation followed by a double proton transfer and a dissociation of the dimer is a self catalytic way from one tautomer to the other.
In solution, the tautomerisation can be done over the dimer. Protic solvents also mediate the proton transfer during the tautomerisation. Like the deprotonation and reprotonation during autoprotolyse can leads to both tautomers.
# Synthesis
Syntheisis from 2-Pyran
2-Pyrane can be obtained by a cyclisation reaction. 2-Pyridone is formed by an exchange reaction with Ammonia from this 2-pyrane.
Syntheisis from Pyridine-N-oxide
Pyridine forms an N-oxide with some oxidation agents for example hydrogen peroxide. This pyridine-N-oxide undergoes a rearrangement reaction to the 2-Pyridone in acetic anhydride.
In the Guareschi-Thorpe condensation cyanoacetamide reacts with a 1,3-diketone to a 2-pyridone.
# Main Research Interests
## Catalytic Activity
After the discovering that 2-Pyridone catalyses the mutarotation of sugars and that 2-pyridone has a large effect on the reaction from activated esters with amines in nonpolar solvent.
Acid or base catalysed reactions should depend in first order on pKa value, but as relative weak acid or base enhances the reaction far more than expected. 4-Pyridone shows no such effect, this leads to the conclusion that the special structure and tautomerisation is the cause for this catalysis.
Neither sugar mutarotation nor ester aminolysis in nonpolar solvent have big impact in synthesis. Because sugar mutarotation takes place even without catalysis and ester aminolysis as source for peptide bonds was seldom used and with activated esters the reaction itself is fast.
Polar solvents enhance the reaction more than the use of 2-pyridone. The normal synthesis for peptides with DCCI or DMAP give good yields and the previous synthesis of phenyl or nitro-phenyl esters can be avoided.
Because of this a direct use of 2-pyridone in ester aminolysis was never the goal of the research. But understanding the simple proton transfer catalysis would be a big step in understanding the principle which is also present in enzyme catalysed reaction. Most of the research was done to understand the activation of the transition state by the 2-pyridone.
Isotope labelling, kinetics and quantum chemical methods were used on the mechanism to determine the rate determining step in the reaction.
The cyclisation of a macrocycle was catalysed with 2-pyridone. A synthesis trick for unwilling substrates is to use molten 2-pyridone as solvent.
## Relation to Base Pairs
2-pyridone dimer compared with base pair
These structures are closely related to the base pairs present in the DNA or RNA. These dimers are sometimes used as simple models for base pairs (in experimental and theoretical studies). The strength of the hydrogen bonds is important for the two strands in DNA and RNA sticking to each other. For the 2-pyridone dimer there are direct measurements of the dimerisation constant and the dimerisation energy which are compared to the calculated ones.
Because of the multiple possible base pair combinations, measurements with the natural base pairs are difficult. If the results of the simple 2-pyridone model give good agreement, these theoretical methods are also suitable for base pairs.
## Coordination Chemistry
2-Pyridone and some derivatives where used as ligands in coordination chemistry. The main point of this chemistry was that 2-pyridone functions as a 1,3-bridged ligand like carboxylate. There is a large number of dimeric complexes. A review with a literature overview can be found at Rawson and Winpenny.
# Analytical Data
## NMR spectroscopy
NMR data of 2-Pyridone
### 1H-NMR
1H-NMR (400 MHz, CD3OD): /ρ = 8.07 (dd,3J = 2.5 Hz,4J = 1.1 Hz, 1H, C-6), 7.98 (dd,3J = 4.0 Hz,3J = 2.0 Hz, 1H, C-3), 7.23 (dd,3J = 2.5 Hz,3J = 2.0 Hz, 1H, C-5), 7.21 (dd,3J = 4.0 Hz,4J = 1.0 Hz, 1H, C-4).
### 13C-NMR
(100.57 MHz, CD3OD): ρ = 155.9 (C-2), 140.8 (C-4), 138.3 (C-6), 125.8 (C-3), 124.4 (C-5)
## UV/Vis spectroscopy
(MeOH):νmax (lg ε) = 226.2 (0.44), 297.6 (0.30).
## IR spectroscopy
(KBr): ν = 3440 cm-1–1 (br, m), 3119 (m), 3072 (m), 2986 (m), 1682 (s), 1649 (vs), 1609 (vs), 1578 (vs), 1540 (s), 1456 (m), 1433 (m), 1364 (w), 1243 (m), 1156 (m), 1098 (m), 983 (m), 926 (w), 781 (s), 730 (w), 612 (w), 560 (w), 554 (w), 526 (m), 476 (m), 451 (w).
## Mass-spectroscopy
EI-MS (70 eV): m/z (%) = 95 (100) , 67 (35) , 51 (4). | 2-Pyridone
Template:Chembox new
2-Pyridone is the chemical compound with the formula C5H4NH(O). This colourless crystalline solid is used in peptide synthesis. It is well known to form hydrogen bonded structures somewhat related to the base-pairing mechanism found in RNA and DNA. It is also a classic case of a molecule that exists as tautomers.
# Structure
The most prominent feature of the 2-pyridone is the amide group, a nitrogen with a hydrogen bound to it and a keto group next to it. In peptides, amino acids are linked by this pattern.
This pattern is responsible for some remarkable physical and chemical properties.
The hydrogen bound to the nitrogen is suitable to form strong hydrogen bonds to other nitrogen- and oxygen-containing species.
# Tautomerism
The hydrogen bond to the nitrogen is also suitable to move to the oxygen. Through hydrogen and electron shift the second tautomer form of the substance is formed. 2-hydroxypyridine is the name for this tautomer. This lactam lactim tautomerism can also be found in other molecules with a similar structure.[1]
## Tautomerism in Solid State
The predominant form in solid state is the 2-pyridone. This fact has been clarified by X-ray crystallography which shows that the hydrogen in solid state is closer to the nitrogen than to the oxygen (because of the low electron density at the hydrogen the exact positioning is difficult) and IR-spectroscopy in which the C=O longitudinal frequency is present and the O-H frequencies are absent.[2][3][4][5]
## Tautomerism in Solution
To determine which of the two tautomeric forms is present in solution has been the subject of many publications. The energy difference seems to be very small and depending on the polarity of the solvent. Nonpolar solvents favour the 2-hydroxypyridine whereas in polar solvents like alcohols and water the 2-pyridone is favoured.[6][7][8][9][10][11][12][13][14]
The energy difference for the two tautomers in the gas phase was measured by IR-spectroscopy to be 2.43 to 3.3 kJ/mol for the solid state and 8.95 kJ/mol and 8.83 kJ/mol for the liquid state.[15][16][17]
## Tautomerisation Mechanism A
The single molecular tautomerisation has a forbidden 1-3 suprafacial transition state and therefore has a high energy barrier for this tautomerisation, which was calculated with theoretical methods to be 125 or 210 kJ/mol. The direct tautomerisation is energetically not favoured. There are other possible mechanisms for this tautomerisation.[16]
# Dimerisation
dimer
The 2-pyridone and the 2-hydroxypyridine can form dimers with two hydrogen bonds[18].
## Aggregation in Solid-state
In solid state the dimeric form is not present; the 2-pyridones form a helical structure over hydrogen bonds. Some substituted 2-pyridones form the dimer in solid state, for example the 5-methyl-3-carbonitrile-2-pyridone. The determination of all these structures was done by X-ray crystallography.
In solid state the hydrogen is located closer to the oxygen so it could be considered to be right to call the colourless crystals in the flask 2-pyridone.[1-5]
## Aggregation in Solution
In solution the dimeric form is present; the ratio of dimerisation is strongly dependent on the polarity of the solvent. Polar and protic solvents interact with the hydrogen bonds and more monomer is formed. hydrophobic effects in unpolar solvents lead to a predominance of the dimere. Also the ratio of the tautomeric forms is dependent on the solvent. All possible tautomers and dimmers can be present and form an equilibrium. The exact measurement of all the equilibrium constants in the system are extremely difficult.[17-27]
(NMR-spectroscopy is a slow method, high resolution IR-spectroscopy in solvent is difficult, the broad absorption in UV-spectroscopy makes it hard to discriminate 3 and more very similar molecules).
Some publications only focus one of the two possible patterns, and neglect the influence of the other. For example to calculate the energy difference of the two tautomeres in nonpolar solution, leads too a wrong results if a large quantity of the substance is on the side of the dimer in an equilibrium.
## Tautomerisation Mechanism B
The direct tautomerisation is energetically not favoured, but a dimerisation followed by a double proton transfer and a dissociation of the dimer is a self catalytic way from one tautomer to the other.
In solution, the tautomerisation can be done over the dimer. Protic solvents also mediate the proton transfer during the tautomerisation. Like the deprotonation and reprotonation during autoprotolyse can leads to both tautomers.
# Synthesis
Syntheisis from 2-Pyran
2-Pyrane can be obtained by a cyclisation reaction. 2-Pyridone is formed by an exchange reaction with Ammonia from this 2-pyrane.
Syntheisis from Pyridine-N-oxide
Pyridine forms an N-oxide with some oxidation agents for example hydrogen peroxide. This pyridine-N-oxide undergoes a rearrangement reaction to the 2-Pyridone in acetic anhydride.
In the Guareschi-Thorpe condensation cyanoacetamide reacts with a 1,3-diketone to a 2-pyridone[19][20].
# Main Research Interests
## Catalytic Activity
After the discovering that 2-Pyridone catalyses the mutarotation of sugars and that 2-pyridone has a large effect on the reaction from activated esters with amines in nonpolar solvent.
Acid or base catalysed reactions should depend in first order on pKa value, but as relative weak acid or base enhances the reaction far more than expected. 4-Pyridone shows no such effect, this leads to the conclusion that the special structure and tautomerisation is the cause for this catalysis.
Neither sugar mutarotation nor ester aminolysis in nonpolar solvent have big impact in synthesis. Because sugar mutarotation takes place even without catalysis and ester aminolysis as source for peptide bonds was seldom used and with activated esters the reaction itself is fast.
Polar solvents enhance the reaction more than the use of 2-pyridone. The normal synthesis for peptides with DCCI or DMAP give good yields and the previous synthesis of phenyl or nitro-phenyl esters can be avoided.
Because of this a direct use of 2-pyridone in ester aminolysis was never the goal of the research. But understanding the simple proton transfer catalysis would be a big step in understanding the principle which is also present in enzyme catalysed reaction. Most of the research was done to understand the activation of the transition state by the 2-pyridone.
Isotope labelling, kinetics and quantum chemical methods were used on the mechanism to determine the rate determining step in the reaction.[21][22]
The cyclisation of a macrocycle was catalysed with 2-pyridone. A synthesis trick for unwilling substrates is to use molten 2-pyridone as solvent.
## Relation to Base Pairs
2-pyridone dimer compared with base pair
These structures are closely related to the base pairs present in the DNA or RNA. These dimers are sometimes used as simple models for base pairs (in experimental and theoretical studies). The strength of the hydrogen bonds is important for the two strands in DNA and RNA sticking to each other. For the 2-pyridone dimer there are direct measurements of the dimerisation constant and the dimerisation energy which are compared to the calculated ones.
Because of the multiple possible base pair combinations, measurements with the natural base pairs are difficult. If the results of the simple 2-pyridone model give good agreement, these theoretical methods are also suitable for base pairs.
## Coordination Chemistry
2-Pyridone and some derivatives where used as ligands in coordination chemistry. The main point of this chemistry was that 2-pyridone functions as a 1,3-bridged ligand like carboxylate. There is a large number of dimeric complexes. A review with a literature overview can be found at Rawson and Winpenny.[23]
# Analytical Data
## NMR spectroscopy
NMR data of 2-Pyridone
### 1H-NMR
1H-NMR (400 MHz, CD3OD): /ρ = 8.07 (dd,3J = 2.5 Hz,4J = 1.1 Hz, 1H, C-6), 7.98 (dd,3J = 4.0 Hz,3J = 2.0 Hz, 1H, C-3), 7.23 (dd,3J = 2.5 Hz,3J = 2.0 Hz, 1H, C-5), 7.21 (dd,3J = 4.0 Hz,4J = 1.0 Hz, 1H, C-4).
### 13C-NMR
(100.57 MHz, CD3OD): ρ = 155.9 (C-2), 140.8 (C-4), 138.3 (C-6), 125.8 (C-3), 124.4 (C-5)
## UV/Vis spectroscopy
(MeOH):νmax (lg ε) = 226.2 (0.44), 297.6 (0.30).
## IR spectroscopy
(KBr): ν = 3440 cm-1–1 (br, m), 3119 (m), 3072 (m), 2986 (m), 1682 (s), 1649 (vs), 1609 (vs), 1578 (vs), 1540 (s), 1456 (m), 1433 (m), 1364 (w), 1243 (m), 1156 (m), 1098 (m), 983 (m), 926 (w), 781 (s), 730 (w), 612 (w), 560 (w), 554 (w), 526 (m), 476 (m), 451 (w).
## Mass-spectroscopy
EI-MS (70 eV): m/z (%) = 95 (100) [M+], 67 (35) [M+ - CO], 51 (4)[C4H3+]. | https://www.wikidoc.org/index.php/2-Pyridone | |
4227b6ad3b0a4822d8f8ce19f2ea558bc4fc22ad | wikidoc | SARS-CoV-2 | SARS-CoV-2
# Overview
The Coronavirus disease-2019 (COVID-19), is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 forms a distinct lineage with bat SARS-like coronaviruses . The virus is closely related (96.3%) to bat coronavirus RaTG13, based on phylogenetic analysis, that belong to the order Nidovirales, family Coronaviridae, genus Betacoronavirus, and subgenus Sarbecovirus . Coronaviruses are enveloped, single-stranded RNA viruses that can infect a wide range of hosts including avian, wild, domestic mammalian species, and humans. Coronaviruses are well known for their ability to mutate rapidly, alter tissue tropism, cross the species barrier, and adapt to different epidemiological situations. Six human coronaviruses have been reported since the 1960s; OC43, 229E, NL63, HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). First case of COVID-19 was reported in Wuhan, Hubei province, China, in December 2019, associated with the Huanan Seafood Wholesale Market. On March 11, 2020 the Novel Coronavirus Disease, COVID-19, was declared a pandemic by the World Health Organization
# Taxonomy
- SARS-CoV-2 belong to the order nidovirale, family coronaviridae.
- Coronaviridae is classified into two subfamilies.
Torovirinae
Coronavirinae
- Torovirinae
- Coronavirinae
- Coronavirinae is further classified on the basis of phylogenetic analysis and genome structure into four genera:
Alpha coronavirus (αCoV).
Beta coronavirus (βCoV).
Gamma coronavirus (γCoV).
Delta coronavirus (δCoV), which contain 17, 12, 2, and 7 unique species, respectively (ICTV 2018).
- Alpha coronavirus (αCoV).
- Beta coronavirus (βCoV).
- Gamma coronavirus (γCoV).
- Delta coronavirus (δCoV), which contain 17, 12, 2, and 7 unique species, respectively (ICTV 2018).
- CoV-2 falls under beta coronavirus.
### Structural Proteins
- Spike (S) Protein
Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases.
Early studies indicate that SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S protein priming.
The spike (S) glycoprotein is a type I transmembrane glycoprotein that plays an important role in mediating viral infection.
The S proteins consist of two subunits, S1 and S2.
The S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.
- Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases.
- Early studies indicate that SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S protein priming.
- The spike (S) glycoprotein is a type I transmembrane glycoprotein that plays an important role in mediating viral infection.
- The S proteins consist of two subunits, S1 and S2.
- The S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.
- Envelope (E) Protein
The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis.
Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins.
Recombinant CoVs lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation.
- The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis.
- Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins.
- Recombinant CoVs lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation.
- Membrane (M) Protein
The CoV membrane (M) protein is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins.
M is located among the S proteins in the virus envelope along with small amounts of E and is the primary driver of the virus budding process.
During assembly of the authentic virion M interacts with itself, with the nucleocapsid protein N, with E and with the S protein.
The M protein has dominant cellular immunogenicity and elicits a strong humoral response which suggests it could serve as a potential target in vaccine design.
- The CoV membrane (M) protein is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins.
- M is located among the S proteins in the virus envelope along with small amounts of E and is the primary driver of the virus budding process.
- During assembly of the authentic virion M interacts with itself, with the nucleocapsid protein N, with E and with the S protein.
- The M protein has dominant cellular immunogenicity and elicits a strong humoral response which suggests it could serve as a potential target in vaccine design.
- Nucleocapsid (N) Protein
The primary function of the nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP) complex called the capsid.
Ribonucleocapsid packaging is a fundamental part of viral self-assembly and replication.
Additionally, the N-protein of the SARS-CoV-2 affects host cell responses and may serve regulatory roles during its viral life cycle.
- The primary function of the nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP) complex called the capsid.
- Ribonucleocapsid packaging is a fundamental part of viral self-assembly and replication.
- Additionally, the N-protein of the SARS-CoV-2 affects host cell responses and may serve regulatory roles during its viral life cycle.
## CORONA VIRUS LIFE CYCLE:
## Attachment and Entry:
- The attachment of the virion to the host cell is associated with the interactions between the S protein and its receptor.
- The sites of receptor binding domains (RBD) within the S1 region of a coronavirus (SARS-CoV-2) S protein is at the C Terminus.
- SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as their receptor
- After binding to the receptor, the virus next step is to gain access to the host cell cytosol.
- This is generally done by cathepsin,TMPRRS2 or some other protease. This is followed by fusion of the viral and cellular membranes.
- S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage important for separating the RBD (Receptor binding domain) and fusion domains of the S protein and the second for exposing the fusion peptide (cleavage at S2′).
- Fusion occurs within acidified endosomes.
- Cleavage at S2′ exposes a fusion peptide that inserts into the membrane, which is followed by joining of two heptad repeats in S2 forming an antiparallel six-helix bundle.The formation of this bundle allows for the mixing of viral and cellular membranes, resulting in fusion and ultimately release of the viral genome into the cytoplasm.
### RNA Replicase Protein Expression:
- The next step in the coronavirus lifecycle is translation and assembly of the viral replicase complexes from the virion genomic RNA.
### Replication and Transcription:
- The translation and assembly of the viral replicase complexes is followed by viral RNA synthesis.
- Viral RNA synthesis produces both genomic and sub-genomic RNAs.
- Sub-genomic RNAs serve as mRNAs for the structural and accessory genes which reside downstream of the replicase polyproteins. All positive-sense sub-genomic RNAs are 3′ co-terminal with the full-length viral genome and thus form a set of nested RNAs, a distinctive property of the order Nidovirales. Both genomic and sub-genomic RNAs are produced through negative-sense intermediates. These negative-strand intermediates are only about 1 % as abundant as their positive-sense counterparts and contain both poly-uridylate and anti-leader sequences.
### Assembly and Release:
- After replication and transcription, the structural proteins of virus ( S,M,E) are translated and then inserted into endoplasmic reticulum. From endoplasmic reticulum they are taken to endoplasmic reticulum-Golgi intermediate compartment.
- Here the N protein encapsidate the viral genome, and bud into membranes of the endoplasmic reticulum-Golgi intermediate compartment containing viral structural proteins, thus forming mature virion.
- Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis.
# Tropism
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, which is lung alveolar epithelial cell .
- SARS-CoV-2 can be detected in multiple organs, including the lungs, heart, liver, brain, pharynx and kidneys.
- Highest levels of SARS-CoV-2 copies per cell were presumed to be detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood.
These findings indicate a broad organotropism of SARS-CoV-2.
- These findings indicate a broad organotropism of SARS-CoV-2.
# Natural Reservoir
- Current evidences suggest that the evolutional origin of SARS-CoV-2 is from bat virus an intermediate host between bats and human might exist.
- Potential intermediate host for SARS-CoV-2 can be pangolin.
- Novel coronaviruses representing two sub-lineages related to SARS-CoV-2 were found in the samples of malytan pangolins.
- The similarity of SARS-CoV-2 to these identified coronaviruses from pangolins is approximately 85.5% to 92.4% in genomes, lower than that to the bat coronavirus RaTG13 (96.2%) 14,62.
- However, the receptor-binding domain of S protein from one sub-lineage of the pangolin coronaviruses shows 97.4% similarity in amino acid sequences to that of SARS-CoV-2, even higher than that to RaTG13 (89.2%). | SARS-CoV-2
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [[1]]; Associate Editor(s)-in-Chief: Syed rizvi, M.B.B.S[1]
# Overview
The Coronavirus disease-2019 (COVID-19), is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). SARS-CoV-2 forms a distinct lineage with bat SARS-like coronaviruses . The virus is closely related (96.3%) to bat coronavirus RaTG13, based on phylogenetic analysis, that belong to the order Nidovirales, family Coronaviridae, genus Betacoronavirus, and subgenus Sarbecovirus . Coronaviruses are enveloped, single-stranded RNA viruses that can infect a wide range of hosts including avian, wild, domestic mammalian species, and humans. Coronaviruses are well known for their ability to mutate rapidly, alter tissue tropism, cross the species barrier, and adapt to different epidemiological situations. Six human coronaviruses have been reported since the 1960s; OC43, 229E, NL63, HKU1, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). First case of COVID-19 was reported in Wuhan, Hubei province, China, in December 2019, associated with the Huanan Seafood Wholesale Market. On March 11, 2020 the Novel Coronavirus Disease, COVID-19, was declared a pandemic by the World Health Organization
# Taxonomy
-
-
-
-
-
-
-
-
-
-
-
- SARS-CoV-2 belong to the order nidovirale, family coronaviridae.[1]
- Coronaviridae is classified into two subfamilies.
Torovirinae
Coronavirinae
- Torovirinae
- Coronavirinae
- Coronavirinae is further classified on the basis of phylogenetic analysis and genome structure into four genera:
Alpha coronavirus (αCoV).
Beta coronavirus (βCoV).
Gamma coronavirus (γCoV).
Delta coronavirus (δCoV), which contain 17, 12, 2, and 7 unique species, respectively (ICTV 2018).
- Alpha coronavirus (αCoV).
- Beta coronavirus (βCoV).
- Gamma coronavirus (γCoV).
- Delta coronavirus (δCoV), which contain 17, 12, 2, and 7 unique species, respectively (ICTV 2018).
- CoV-2 falls under beta coronavirus.
### Structural Proteins
- Spike (S) Protein [2][3]
Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases.
Early studies indicate that SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S protein priming.[7][8]
The spike (S) glycoprotein is a type I transmembrane glycoprotein that plays an important role in mediating viral infection.
The S proteins consist of two subunits, S1 and S2.
The S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.[9]
- Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases.
- Early studies indicate that SARS-CoV-2 uses the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry and transmembrane protease serine 2 (TMPRSS2) for S protein priming.[7][8]
- The spike (S) glycoprotein is a type I transmembrane glycoprotein that plays an important role in mediating viral infection.
- The S proteins consist of two subunits, S1 and S2.
- The S1 subunit binds the cellular receptor through its receptor-binding domain (RBD), followed by conformational changes in the S2 subunit, which allows the fusion peptide to insert into the host target cell membrane.[9]
- Envelope (E) Protein[4]
The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis.[10]
Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins.[11]
Recombinant CoVs lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation.[12]
- The CoV envelope (E) protein is a small, integral membrane protein involved in several aspects of the virus’ life cycle, such as assembly, budding, envelope formation, and pathogenesis.[10]
- Recent studies have expanded on its structural motifs and topology, its functions as an ion-channelling viroporin, and its interactions with both other CoV proteins and host cell proteins.[11]
- Recombinant CoVs lacking E exhibit significantly reduced viral titres, crippled viral maturation, or yield propagation incompetent progeny, demonstrating the importance of E in virus production and maturation.[12]
- Membrane (M) Protein [5]
The CoV membrane (M) protein is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins.
M is located among the S proteins in the virus envelope along with small amounts of E and is the primary driver of the virus budding process.
During assembly of the authentic virion M interacts with itself, with the nucleocapsid protein N, with E and with the S protein.
The M protein has dominant cellular immunogenicity and elicits a strong humoral response which suggests it could serve as a potential target in vaccine design.[14] [15]
- The CoV membrane (M) protein is a component of the viral envelope that plays a central role in virus morphogenesis and assembly via its interactions with other viral proteins.
- M is located among the S proteins in the virus envelope along with small amounts of E and is the primary driver of the virus budding process.
- During assembly of the authentic virion M interacts with itself, with the nucleocapsid protein N, with E and with the S protein.
- The M protein has dominant cellular immunogenicity and elicits a strong humoral response which suggests it could serve as a potential target in vaccine design.[14] [15]
- Nucleocapsid (N) Protein[16]
The primary function of the nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP) complex called the capsid.
Ribonucleocapsid packaging is a fundamental part of viral self-assembly and replication.
Additionally, the N-protein of the SARS-CoV-2 affects host cell responses and may serve regulatory roles during its viral life cycle.
- The primary function of the nucleocapsid (N) protein is to package the viral RNA genome within the viral envelope into a ribonucleoprotein (RNP) complex called the capsid.
- Ribonucleocapsid packaging is a fundamental part of viral self-assembly and replication.
- Additionally, the N-protein of the SARS-CoV-2 affects host cell responses and may serve regulatory roles during its viral life cycle.
## CORONA VIRUS LIFE CYCLE:
## Attachment and Entry:
- The attachment of the virion to the host cell is associated with the interactions between the S protein and its receptor.
- The sites of receptor binding domains (RBD) within the S1 region of a coronavirus (SARS-CoV-2) S protein is at the C Terminus.[18]
- SARS-CoV use angiotensin-converting enzyme 2 (ACE2) as their receptor[19]
- After binding to the receptor, the virus next step is to gain access to the host cell cytosol.
- This is generally done by cathepsin,TMPRRS2 or some other protease. This is followed by fusion of the viral and cellular membranes.
- S protein cleavage occurs at two sites within the S2 portion of the protein, with the first cleavage important for separating the RBD (Receptor binding domain) and fusion domains of the S protein [20] and the second for exposing the fusion peptide (cleavage at S2′).
- Fusion occurs within acidified endosomes.
- Cleavage at S2′ exposes a fusion peptide that inserts into the membrane, which is followed by joining of two heptad repeats in S2 forming an antiparallel six-helix bundle[21].The formation of this bundle allows for the mixing of viral and cellular membranes, resulting in fusion and ultimately release of the viral genome into the cytoplasm.
### RNA Replicase Protein Expression:
- The next step in the coronavirus lifecycle is translation and assembly of the viral replicase complexes from the virion genomic RNA.
### Replication and Transcription:
- The translation and assembly of the viral replicase complexes is followed by viral RNA synthesis.
- Viral RNA synthesis produces both genomic and sub-genomic RNAs.
- Sub-genomic RNAs serve as mRNAs for the structural and accessory genes which reside downstream of the replicase polyproteins. All positive-sense sub-genomic RNAs are 3′ co-terminal with the full-length viral genome and thus form a set of nested RNAs, a distinctive property of the order Nidovirales. Both genomic and sub-genomic RNAs are produced through negative-sense intermediates. These negative-strand intermediates are only about 1 % as abundant as their positive-sense counterparts and contain both poly-uridylate and anti-leader sequences.[22]
### Assembly and Release:
- After replication and transcription, the structural proteins of virus ( S,M,E) are translated and then inserted into endoplasmic reticulum. From endoplasmic reticulum they are taken to endoplasmic reticulum-Golgi intermediate compartment.[23]
- Here the N protein encapsidate the viral genome, and bud into membranes of the endoplasmic reticulum-Golgi intermediate compartment containing viral structural proteins, thus forming mature virion.[24]
- Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis.
# Tropism
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) preferentially infects cells in the respiratory tract, which is lung alveolar epithelial cell .[25][26]
- SARS-CoV-2 can be detected in multiple organs, including the lungs, heart, liver, brain, pharynx and kidneys.[27]
- Highest levels of SARS-CoV-2 copies per cell were presumed to be detected in the respiratory tract, and lower levels were detected the kidneys, liver, heart, brain, and blood.
These findings indicate a broad organotropism of SARS-CoV-2.[28]
- These findings indicate a broad organotropism of SARS-CoV-2.[28]
# Natural Reservoir
- Current evidences suggest that the evolutional origin of SARS-CoV-2 is from bat virus an intermediate host between bats and human might exist.[29][30]
- Potential intermediate host for SARS-CoV-2 can be pangolin.
- Novel coronaviruses representing two sub-lineages related to SARS-CoV-2 were found in the samples of malytan pangolins.[31]
- The similarity of SARS-CoV-2 to these identified coronaviruses from pangolins is approximately 85.5% to 92.4% in genomes, lower than that to the bat coronavirus RaTG13 (96.2%) 14,62.
- However, the receptor-binding domain of S protein from one sub-lineage of the pangolin coronaviruses shows 97.4% similarity in amino acid sequences to that of SARS-CoV-2, even higher than that to RaTG13 (89.2%).[32]
- | https://www.wikidoc.org/index.php/2019-nCoV | |
f564af936784591f293ecd0accd3db290a704b1d | wikidoc | 5-MeO-DALT | 5-MeO-DALT
5-MeO-DALT (N,N-diallyl-5-methoxytryptamine) is a psychedelic tryptamine believed to be first synthesized by Alexander Shulgin.
# Chemistry
The full name of the chemical is N-allyl-N-prop-2-en-1-amine. It is very closely related to the compound 5-MeO-DPT and DALT.
# Dosage
5-MeO-DALT is usually taken orally at dosages of 12-25mg.
# Effects
5-MeO-DALT produces rapid, intense entheogenic effects, and it is very short-acting; effects are usually over within 2-4 hours. According to many users, the compound is said to be completely void of visual/hallucinogenic activity, unlike other closely related substances.
# Dangers
There have been no reported deaths or hospitalizations from 5-MeO-DALT, but its safety profile is unknown.
# Legality
5-MeO-DALT is unscheduled and uncontrolled in the United States, but possession and sales of 5-MeO-DALT could be prosecuted under the Federal Analog Act because of its structural similarities to other Schedule I substances. | 5-MeO-DALT
5-MeO-DALT (N,N-diallyl-5-methoxytryptamine) is a psychedelic tryptamine believed to be first synthesized by Alexander Shulgin.
# Chemistry
The full name of the chemical is N-allyl-N-[2-(5-methoxy-1H-indol-3-yl)ethyl]prop-2-en-1-amine. It is very closely related to the compound 5-MeO-DPT and DALT.
# Dosage
5-MeO-DALT is usually taken orally at dosages of 12-25mg.
# Effects
5-MeO-DALT produces rapid, intense entheogenic effects, and it is very short-acting; effects are usually over within 2-4 hours. According to many users, the compound is said to be completely void of visual/hallucinogenic activity, unlike other closely related substances.
# Dangers
There have been no reported deaths or hospitalizations from 5-MeO-DALT, but its safety profile is unknown.
# Legality
5-MeO-DALT is unscheduled and uncontrolled in the United States, but possession and sales of 5-MeO-DALT could be prosecuted under the Federal Analog Act because of its structural similarities to other Schedule I substances.
# External links
- Erowid 5-MeO-DALT vault
- Bluelight.ru 5-MeO-DALT information
Template:Entactogens
Template:Tryptamines
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/5-MeO-DALT | |
7556d461a583f6a872ade517b9389bd199bec7ff | wikidoc | 5-MeO-MiPT | 5-MeO-MiPT
5-MeO-MiPT is a psychedelic and hallucinogenic drug, used by some as an entheogen. It has structural and pharmacodynamic properties similar to the drugs 5-MeO-DiPT and MiPT.
# Chemistry
5-MeO-MiPT is in a class of compounds commonly known as tryptamines, and is the N-methyl-N-isopropyl homologue of the organic psychedelic, 5-MeO-DMT. The full name of the chemical is 5-methoxy-N-methyl-N-isopropyltryptamine.
# Effects
Taken orally, 5-MeO-MiPT produces psychedelic effects that can last 4-6 hours. When smoked, the effects are nearly instantaneous and can last up to 2 hours.
This is an anologue of the more popular drug 5-MeO-DiPT (foxy methoxy) and has been dubbed "moxy" in the RC community. Some users report the tactile effects of moxy without some of the unwanted side effects. At higher doses it becomes much more psychedelic and less tactile. But at doses of 4-10 milligrams users find 5-MeO-MiPT to be a very euphoric and tactile chemical.
# Dosage
Orally, 5-MeO-MiPT is active at 4-6 mg. The drug can also be smoked, but unlike most other tryptamines, this route requires a much higher dosage. 12-20mg is usually smoked. It typically produces a very strong odor.
Some users report activity as low as 1mg while others report no activity up to 20mg, this compound seems to be highly sensitive to the individual and any potential researchers should keep this in mind. Titrating the dose would be especially important with this compound.
Some users report little to no visual activity until doses of 10mg or higher are taken. This chemical proves very useful for opening up and expressing ones self much like MDMA (3,4-methylenedioxymethamphetamine) and may be a useful chemical in psychedelic therapy.
# Pharmacology
The mechanism that produces the hallucinogenic and entheogenic effects of 5-MeO-MiPT is unknown, though is most likely attriutable to 5HT2A receptor agonsim, among others.
# Dangers
The toxicity of 5-MeO-MiPT is not known but as with all research chemicals doses should be carefully weighed on an accurate milligram scale and users should take caution because overdoses are not listed.
# Popularity
5-MeO-MiPT is rare on the black market, but is available through research chemical suppliers.
# Legality
5-MeO-MiPT is unscheduled and unregulated in the United States, however its close similarity in structure and effects to 5-MeO-DiPT could potentially subject possession and sale of 5-MeO-MiPT to prosecution under the Federal Analog Act. This seems to be the tact the federal government is taking in the wake of the DEA's Operation Web Tryp. A series of Court Cases in the US involving the prosecution of several online vendors in ongoing as of 2004.
5-MeO-MiPT is a Class A drug in the United Kingdom. | 5-MeO-MiPT
5-MeO-MiPT is a psychedelic and hallucinogenic drug, used by some as an entheogen. It has structural and pharmacodynamic properties similar to the drugs 5-MeO-DiPT and MiPT.
# Chemistry
5-MeO-MiPT is in a class of compounds commonly known as tryptamines, and is the N-methyl-N-isopropyl homologue of the organic psychedelic, 5-MeO-DMT. The full name of the chemical is 5-methoxy-N-methyl-N-isopropyltryptamine.
# Effects
Taken orally, 5-MeO-MiPT produces psychedelic effects that can last 4-6 hours. When smoked, the effects are nearly instantaneous and can last up to 2 hours.
This is an anologue of the more popular drug 5-MeO-DiPT (foxy methoxy) and has been dubbed "moxy" in the RC community. Some users report the tactile effects of moxy without some of the unwanted side effects. At higher doses it becomes much more psychedelic and less tactile. But at doses of 4-10 milligrams users find 5-MeO-MiPT to be a very euphoric and tactile chemical.
# Dosage
Orally, 5-MeO-MiPT is active at 4-6 mg. The drug can also be smoked, but unlike most other tryptamines, this route requires a much higher dosage. 12-20mg is usually smoked. It typically produces a very strong odor.
Some users report activity as low as 1mg while others report no activity up to 20mg, this compound seems to be highly sensitive to the individual and any potential researchers should keep this in mind. Titrating the dose would be especially important with this compound.
Some users report little to no visual activity until doses of 10mg or higher are taken. This chemical proves very useful for opening up and expressing ones self much like MDMA (3,4-methylenedioxymethamphetamine) and may be a useful chemical in psychedelic therapy.
# Pharmacology
The mechanism that produces the hallucinogenic and entheogenic effects of 5-MeO-MiPT is unknown, though is most likely attriutable to 5HT2A receptor agonsim, among others.
# Dangers
The toxicity of 5-MeO-MiPT is not known but as with all research chemicals doses should be carefully weighed on an accurate milligram scale and users should take caution because overdoses are not listed.
# Popularity
5-MeO-MiPT is rare on the black market, but is available through research chemical suppliers.
# Legality
5-MeO-MiPT is unscheduled and unregulated in the United States, however its close similarity in structure and effects to 5-MeO-DiPT could potentially subject possession and sale of 5-MeO-MiPT to prosecution under the Federal Analog Act. This seems to be the tact the federal government is taking in the wake of the DEA's Operation Web Tryp. A series of Court Cases in the US involving the prosecution of several online vendors in ongoing as of 2004.
5-MeO-MiPT is a Class A drug in the United Kingdom. | https://www.wikidoc.org/index.php/5-MeO-MIPT | |
db62d464504b60921bb0d3d52f18087d364f8a6e | wikidoc | Nelarabine | Nelarabine
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Nelarabine is an antineoplastic agent that is FDA approved for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, thrombocytopenia, neutropenia, leukopenia, nausea, diarrhea, vomiting, constipation, fatigue, pyrexia, cough, dyspnea, somnolence, dizziness, peripheral neurologic disorders, hypoesthesia, headache, and paresthesia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of nelarabine is 1500 mg/m(2) administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in adults has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
- Dosing Information
- The recommended dose of nelarabine is 1500 milligrams/square meter (mg/m(2)) administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in adults has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nelarabine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelarabine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended pediatric dose of nelarabine is 650 milligrams/square meter (mg/m(2)) administered intravenously over 1 hour daily for 5 consecutive days and repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in pediatric patients has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
- The recommended pediatric dose of nelarabine is 650 milligrams/square meter (mg/m(2)) administered intravenously over 1 hour daily for 5 consecutive days and repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in pediatric patients has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nelarabine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelarabine in pediatric patients.
# Contraindications
- None.
# Warnings
Neurologic Adverse Reactions
- Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ARRANON should be closely observed for signs and symptoms of neurologic toxicity. Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome.
- Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.
Hematologic Adverse Reactions
- Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia, have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly.
Pregnancy
Pregnancy Category D
- ARRANON can cause fetal harm when administered to a pregnant woman.
- Nelarabine administered during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits.
- There are no adequate and well-controlled studies of ARRANON in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Hyperuricemia
- Patients receiving ARRANON should receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumor lysis syndrome. Consideration should be given to the use of allopurinol in patients at risk of hyperuricemia.
Vaccinations
- Administration of live vaccines to immunocompromised patients should be avoided.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Neurologic
- Hematologic
- Hyperuricemia
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- ARRANON was studied in 459 patients in Phase I and Phase II clinical trials.
- Adults: The safety profile of ARRANON is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) trial and an adult chronic lymphocytic leukemia trial.
- The most common adverse reactions in adults, regardless of causality, were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia.
- The most common adverse reactions in adults, by System Organ Class, regardless of causality, including severe or life-threatening adverse reactions (NCI Common Toxicity Criteria Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 1.
- Other Adverse Events: Blurred vision was also reported in 4% of adult patients.
- There was a single report of biopsy-confirmed progressive multifocal leukoencephalopathy in the adult patient population.
- Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 76% of adult patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥2%) in adult patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 2.
- One patient had a fatal neurologic adverse reaction, cerebral hemorrhage/coma/leukoencephalopathy.
- Most nervous system adverse reactions in the adult patients were evaluated as Grade 1 or 2. The additional Grade 3 adverse reactions in adult patients, regardless of causality, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions, regardless of causality, were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).
- The other neurologic adverse reactions, regardless of causality, reported as Grade 1, 2, or unknown in adult patients were abnormal coordination, burning sensation, disturbance in attention, dysarthria, hyporeflexia, neuropathic pain, nystagmus, peroneal nerve palsy, sciatica, sensory disturbance, sinus headache, and speech disorder, each reported in one patient (1%).
- Pediatrics: The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) treatment trial.
- The most common adverse reactions in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non-hematologic adverse reactions in pediatric patients, the most frequent adverse reactions reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.
- The most common adverse reactions in pediatric patients, by System Organ Class, regardless of causality, including severe or life threatening adverse reactions (NCI Common Toxicity Criteria Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 3.
- Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 42% of pediatric patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥2%) in pediatric patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 4.
- The other Grade 3 neurologic adverse reaction in pediatric patients, regardless of causality, was hypertonia reported in 1 patient (1%). The additional Grade 4 neurologic adverse reactions, regardless of causality, were 3rd nerve paralysis, and 6th nerve paralysis, each reported in 1 patient (1%).
- The other neurologic adverse reactions, regardless of causality, reported as Grade 1, 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in 1 patient (1%).
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of ARRANON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Infections and Infestations: Fatal opportunistic infections.
- Metabolism and Nutrition Disorders: Tumor lysis syndrome.
- Nervous System Disorders: Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
- Musculoskeletal and Connective Disorders: Rhabdomyolysis, blood creatine phosphokinase increased.
# Drug Interactions
- Administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- ARRANON can cause fetal harm when administered to a pregnant woman. Nelarabine administered to rabbits during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations at doses ≥360 mg/m2/day (8-hour IV infusion; approximately ¼ the adult dose compared on a mg/m2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,400 mg/m2/day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given ≥1,200 mg/m2/day (approximately ¾ the adult dose), while absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification was seen at all doses. Maternal body weight gain and fetal body weights were reduced in rabbits given 3,400 mg/m2/day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses.
- There are no adequate and well-controlled studies of ARRANON in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nelarabine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Nelarabine during labor and delivery.
### Nursing Mothers
- It is not known whether nelarabine or ara-G are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ARRANON, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of ARRANON has been established in pediatric patients.
### Geriatic Use
- Clinical studies of ARRANON did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In an exploratory analysis, increasing age, especially age 65 years and older, appeared to be associated with increased rates of neurologic adverse reactions. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
- There is no FDA guidance on the use of Nelarabine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Nelarabine with respect to specific racial populations.
### Renal Impairment
- Ara-G clearance decreased as renal function decreased. Because the risk of adverse reactions to this drug may be greater in patients with moderate (CLcr 30 to 50 mL/min) or severe (CLcr <30 mL/min) renal impairment, these patients should be closely monitored for toxicities when treated with ARRANON.
### Hepatic Impairment
- The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated. Because the risk of adverse reactions to this drug may be greater in patients with severe hepatic impairment (total bilirubin >3 times upper limit of normal), these patients should be closely monitored for toxicities when treated with ARRANON.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nelarabine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Nelarabine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Recommended Dosage
- This product is for intravenous use only.
- The recommended duration of treatment for adult and pediatric patients has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Adult Dosage: The recommended adult dose of ARRANON is 1,500 mg/m² administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. ARRANON is administered undiluted.
- Pediatric Dosage: The recommended pediatric dose of ARRANON is 650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. ARRANON is administered undiluted.
Dosage Modification
- Administration of ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater. Dosage may be delayed for other toxicity including hematologic toxicity.
Adjustment of Dose in Special Populations
- ARRANON has not been studied in patients with renal or hepatic dysfunction. No dose adjustment is recommended for patients with a creatinine clearance (CLcr) ≥50 mL/min. There are insufficient data to support a dose recommendation for patients with a CLcr <50 mL/min.
Prevention of Hyperuricemia
- Appropriate measures (e.g., hydration, urinealkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia.
Instructions for Handling, Preparation, and Administration
- Handling: ARRANON is a cytotoxic agent. Caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. Proper aseptic technique should be used. Guidelines for proper handling and disposal of anticancer drugs have been published.
- Preparation and Administration: Do not dilute ARRANON prior to administration. The appropriate dose of ARRANON is transferred into polyvinylchloride (PVC) infusion bags or glass containers and administered as a 2-hour infusion in adult patients and as a 1-hour infusion in pediatric patients.
- Prior to administration, inspect the drug product visually for particulate matter and discoloration.
- Stability: ARRANON Injection is stable in polyvinylchloride (PVC) infusion bags and glass containers for up to 8 hours at up to 30° C.
DOSAGE FORMS AND STRENGTHS
- 250 mg/50 mL (5 mg/mL) vial
### Monitoring
- Severe neurologic adverse reactions have been reported with the use of ARRANON®. Close monitoring for neurologic adverse reactions is strongly recommended, and ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater.
- Complete blood counts including platelets should be monitored regularly for hematologic reactions.
- Closely monitor patients with moderate or severe renal impairment for toxicities.
- Closely monitor patients with severe hepatic impairment for toxicities.
# IV Compatibility
- There is limited information regarding IV Compatibility of Nelarabine in the drug label.
# Overdosage
- There is no known antidote for overdoses of ARRANON. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death. In the event of overdose, supportive care consistent with good clinical practice should be provided.
- Nelarabine has been administered in clinical trials up to a dose of 2,900 mg/m2 on Days 1, 3, and 5 to 2 adult patients. At a dose of 2,200 mg/m2 given on Days 1, 3, and 5 every 21 days, 2 patients developed a significant Grade 3 ascending sensory neuropathy. MRI evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.
# Pharmacology
## Mechanism of Action
Nelarabine is a prodrug of the deoxyguanosine analogue 9-β-D-arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5’-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.
## Structure
- ARRANON (nelarabine) is a prodrug of the cytotoxic deoxyguanosine analogue, 9-β-D-arabinofuranosylguanine (ara-G).
- The chemical name for nelarabine is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27. Nelarabine has the following structural formula:
- Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209° and 217° C.
- ARRANON Injection is supplied as a clear, colorless, sterile solution in glass vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. ARRANON is intended for intravenous infusion.
- Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nelarabine in the drug label.
## Pharmacokinetics
- Absorption: Following intravenous administration of nelarabine to adult patients with refractory leukemia or lymphoma, plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G. Mean plasma nelarabine and ara-G Cmax values were 5.0 ± 3.0 mcg/mL and 31.4 ± 5.6 mcg/mL, respectively, after a 1,500 mg/m2 nelarabine dose infused over 2 hours in adult patients. The area under the concentration-time curve (AUC) of ara-G is 37 times higher than that for nelarabine on Day 1 after nelarabine IV infusion of 1,500 mg/m2 dose (162 ± 49 mcg.h/mL versus 4.4 ± 2.2 mcg.h/mL, respectively). Comparable Cmax and AUC values were obtained for nelarabine between Days 1 and 5 at the nelarabine adult dosage of 1,500 mg/m2, indicating that nelarabine does not accumulate after multiple-dosing. There are not enough ara-G data to make a comparison between Day 1 and Day 5. After a nelarabine adult dose of 1,500 mg/m2, intracellular Cmax for ara-GTP appeared within 3 to 25 hours on Day 1. Exposure (AUC) to intracellular ara-GTP was 532 times higher than that for nelarabine and 14 times higher than that for ara-G (2,339 ± 2,628 mcg.h/mL versus 4.4 ± 2.2 mcg.h/mL and 162 ± 49 mcg.h/mL, respectively). Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated.
- Distribution: Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, VSS values were 197 ± 216 L/m2 in adult patients. For ara-G, VSS/F values were 50 ± 24 L/m2 in adult patients.
- Nelarabine and ara-G are not substantially bound to human plasma proteins (<25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 400 μM.
- Metabolism: The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid.
- Excretion: Nelarabine and ara-G are partially eliminated by the kidneys. Mean urinary excretion of nelarabine and ara-G was 6.6 ± 4.7% and 27 ± 15% of the administered dose, respectively, in 28 adult patients over the 24 hours after nelarabine infusion on Day 1. Renal clearance averaged 24 ± 23 L/h for nelarabine and 6.2 ± 5.0 L/h for ara-G in 21 adult patients. Combined Phase I pharmacokinetic data at nelarabine doses of 199 to 2,900 mg/m2 (n = 66 adult patients) indicate that the mean clearance (CL) of nelarabine is 197 ± 189 L/h/m2 on Day 1. The apparent clearance of ara-G (CL/F) is 10.5 ± 4.5 L/h/m2 on Day 1. Nelarabine and ara-G are rapidly eliminated from plasma with a mean half-life of 18 minutes and 3.2 hours, respectively, in adult patients.
- Pediatrics: No pharmacokinetic data are available in pediatric patients at the once-daily 650 mg/m2 nelarabine dosage. Combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2 indicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259 ± 409 L/h/m2 versus 197 ± 189 L/h/m2, respectively) (n = 66 adults, n = 22 pediatric patients) on Day 1. The apparent clearance of ara-G (CL/F) is comparable between the two groups (10.5 ± 4.5 L/h/m2 in adult patients and 11.3 ± 4.2 L/h/m2 in pediatric patients) on Day 1. Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, VSS values were 213 ± 358 L/m2 in pediatric patients. For ara-G, VSS/F values were 33 ± 9.3 L/m2 in pediatric patients. Nelarabine and ara-G are rapidly eliminated from plasma in pediatric patients, with a half-life of 13 minutes and 2 hours, respectively.
- Effect of Age: Age has no effect on the pharmacokinetics of nelarabine or ara-G in adults. Decreased renal function, which is more common in the elderly, may reduce ara-G clearance.
- Effect of Gender: Gender has no effect on nelarabine or ara-G pharmacokinetics.
- Effect of Race: In general, nelarabine mean clearance and volume of distribution values tend to be higher in whites (n = 63) than in blacks (by about 10%) (n = 15). The opposite is true for ara-G; mean apparent clearance and volume of distribution values tend to be lower in whites than in blacks (by about 15% to 20%). No differences in safety or effectiveness were observed between these groups.
- Effect of Renal Impairment: The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired or hemodialyzed patients. Nelarabine is excreted by the kidney to a small extent (5% to 10% of the administered dose). Ara-G is excreted by the kidney to a greater extent (20% to 30% of the administered nelarabine dose). In the combined Phase I trials, patients were categorized into 3 groups: normal with CLcr >80 mL/min (n = 67), mild with CLcr = 50 to 80 mL/min (n = 15), and moderate with CLcr <50 mL/min (n = 3). The mean apparent clearance (CL/F) of ara-G was about 15% and 40% lower in patients with mild and moderate renal impairment, respectively, than in patients with normal renal function. No differences in safety or effectiveness were observed.
- Effect of Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated.
- Drug Interactions: Cytochrome P450: Nelarabine and ara-G did not significantly inhibit the activities of the human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at concentrations of nelarabine and ara-G up to 100 μM.
- Fludarabine: Administration of fludarabine 30 mg/m2 as a 30-minute infusion 4 hours before a 1,200-mg/m2 infusion of nelarabine did not affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP in 12 patients with refractory leukemia.
Pentostatin: There is in vitro evidence that pentostatin is a strong inhibitor of adenosine deaminase. Inhibition of adenosine deaminase may result in a reduction in the conversion of the prodrug nelarabine to its active moiety and consequently in a reduction in efficacy of nelarabine and/or change in adverse reaction profile of either drug.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity testing of nelarabine has not been done. However, nelarabine was mutagenic when tested in vitro in L5178Y/TK mouse lymphoma cells with and without metabolic activation. No studies have been conducted in animals to assess genotoxic potential or effects on fertility. The effect on human fertility is unknown.
# Clinical Studies
- The safety and efficacy of ARRANON were evaluated in two open-label, single-arm, multicenter trials.
Adult Clinical Trial
- The safety and efficacy of ARRANON in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that had relapsed following or was refractory to at least two prior induction regimens. A 1,500-mg/m2 dose of ARRANON was administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with ARRANON. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with ≥2 prior inductions, the age range was 16 to 65 years (mean 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNS) disease were not eligible.
- Complete response (CR) in this trial was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without complete hematologic recovery (CR*) was also assessed. The results of the trial for patients who had received ≥2 prior inductions are shown in Table 5.
- The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to CR plus CR- ranged from 2.9 to 11.7 weeks.
Pediatric Clinical Trial
- The safety and efficacy of ARRANON in pediatric patients were studied in a clinical trial which included patients aged 21 years and younger, who had relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with 650 mg/m2/day of ARRANON administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 6). Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with ARRANON.
- The 84 patients ranged in age from 2.5 to 21.7 years (overall mean: 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). The majority (77%) of patients had a diagnosis of T-ALL.
- Complete response (CR) in this trial was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without full hematologic recovery (CR*) was also assessed as a meaningful outcome in this heavily pretreated population. Duration of response is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results are presented in Table 7.
- The mean number of days on therapy was 46 days (range: 7 to 129 days). Median time to CR plus CR- was 3.4 weeks (95% CI: 3.0, 3.7).
# How Supplied
- ARRANON Injection is supplied as a clear, colorless, sterile solution in Type I, clear glass vials with a gray bromobutyl rubber stopper (not made with natural rubber latex) and a red snap-off aluminum seal. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. Vials (NDC 0007-4401-01) are available in the following carton size:
- NDC 0007-4401-06 (package of 6)
## Storage
- Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information. However, inform the patients of the following:
- Since patients receiving nelarabine therapy may experience somnolence, they should be cautioned about operating hazardous machinery, including automobiles.
- Patients should be instructed to contact their physician if they experience new or worsening symptoms of peripheral neuropathy. These signs and symptoms include: tingling or numbness in fingers, hands, toes, or feet; difficulty with the fine motor coordination tasks such as buttoning clothing; unsteadiness while walking; weakness arising from a low chair; weakness in climbing stairs; increased tripping while walking over uneven surfaces.
- Patients should be instructed that seizures have been known to occur in patients who receive nelarabine. If a seizure occurs, the physician administering ARRANON should be promptly informed.
- Patients who develop fever or signs of infection while on therapy should notify their physician promptly.
- Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breastfeeding during treatment with ARRANON.
# Precautions with Alcohol
- Alcohol-Nelarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Arranon
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Nelarabine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2];Aparna Vuppala, M.B.B.S. [3]
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# Black Box Warning
# Overview
Nelarabine is an antineoplastic agent that is FDA approved for the treatment of patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma whose disease has not responded to or has relapsed following treatment with at least two chemotherapy regimens. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, thrombocytopenia, neutropenia, leukopenia, nausea, diarrhea, vomiting, constipation, fatigue, pyrexia, cough, dyspnea, somnolence, dizziness, peripheral neurologic disorders, hypoesthesia, headache, and paresthesia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of nelarabine is 1500 mg/m(2) administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in adults has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
- Dosing Information
- The recommended dose of nelarabine is 1500 milligrams/square meter (mg/m(2)) administered intravenously over 2 hours on days 1, 3, and 5 repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in adults has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nelarabine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelarabine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- The recommended pediatric dose of nelarabine is 650 milligrams/square meter (mg/m(2)) administered intravenously over 1 hour daily for 5 consecutive days and repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in pediatric patients has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
- The recommended pediatric dose of nelarabine is 650 milligrams/square meter (mg/m(2)) administered intravenously over 1 hour daily for 5 consecutive days and repeated every 21 days. Nelarabine is administered undiluted. The recommended duration of treatment in pediatric patients has not been established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Appropriate measures must be taken to prevent hyperuricemia of tumor lysis syndrome (eg, hydration, urine alkalinization, and prophylaxis with allopurinol).
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Nelarabine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Nelarabine in pediatric patients.
# Contraindications
- None.
# Warnings
Neurologic Adverse Reactions
- Neurotoxicity is the dose-limiting toxicity of nelarabine. Patients undergoing therapy with ARRANON should be closely observed for signs and symptoms of neurologic toxicity. Common signs and symptoms of nelarabine-related neurotoxicity include somnolence, confusion, convulsions, ataxia, paresthesias, and hypoesthesia. Severe neurologic toxicity can manifest as coma, status epilepticus, craniospinal demyelination, or ascending neuropathy similar in presentation to Guillain-Barré syndrome.
- Patients treated previously or concurrently with intrathecal chemotherapy or previously with craniospinal irradiation may be at increased risk for neurologic adverse events.
Hematologic Adverse Reactions
- Leukopenia, thrombocytopenia, anemia, and neutropenia, including febrile neutropenia, have been associated with nelarabine therapy. Complete blood counts including platelets should be monitored regularly.
Pregnancy
Pregnancy Category D
- ARRANON can cause fetal harm when administered to a pregnant woman.
- Nelarabine administered during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations in rabbits.
- There are no adequate and well-controlled studies of ARRANON in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Hyperuricemia
- Patients receiving ARRANON should receive intravenous hydration according to standard medical practice for the management of hyperuricemia in patients at risk for tumor lysis syndrome. Consideration should be given to the use of allopurinol in patients at risk of hyperuricemia.
Vaccinations
- Administration of live vaccines to immunocompromised patients should be avoided.
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed in greater detail in other sections of the label:
- Neurologic
- Hematologic
- Hyperuricemia
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- ARRANON was studied in 459 patients in Phase I and Phase II clinical trials.
- Adults: The safety profile of ARRANON is based on data from 103 adult patients treated with the recommended dose and schedule in 2 studies: an adult T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) trial and an adult chronic lymphocytic leukemia trial.
- The most common adverse reactions in adults, regardless of causality, were fatigue; gastrointestinal (GI) disorders (nausea, diarrhea, vomiting, and constipation); hematologic disorders (anemia, neutropenia, and thrombocytopenia); respiratory disorders (cough and dyspnea); nervous system disorders (somnolence and dizziness); and pyrexia.
- The most common adverse reactions in adults, by System Organ Class, regardless of causality, including severe or life-threatening adverse reactions (NCI Common Toxicity Criteria Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 1.
- Other Adverse Events: Blurred vision was also reported in 4% of adult patients.
- There was a single report of biopsy-confirmed progressive multifocal leukoencephalopathy in the adult patient population.
- Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 76% of adult patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥2%) in adult patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 2.
- One patient had a fatal neurologic adverse reaction, cerebral hemorrhage/coma/leukoencephalopathy.
- Most nervous system adverse reactions in the adult patients were evaluated as Grade 1 or 2. The additional Grade 3 adverse reactions in adult patients, regardless of causality, were aphasia, convulsion, hemiparesis, and loss of consciousness, each reported in 1 patient (1%). The additional Grade 4 adverse reactions, regardless of causality, were cerebral hemorrhage, coma, intracranial hemorrhage, leukoencephalopathy, and metabolic encephalopathy, each reported in one patient (1%).
- The other neurologic adverse reactions, regardless of causality, reported as Grade 1, 2, or unknown in adult patients were abnormal coordination, burning sensation, disturbance in attention, dysarthria, hyporeflexia, neuropathic pain, nystagmus, peroneal nerve palsy, sciatica, sensory disturbance, sinus headache, and speech disorder, each reported in one patient (1%).
- Pediatrics: The safety profile for children is based on data from 84 pediatric patients treated with the recommended dose and schedule in a T-cell acute lymphoblastic leukemia (T-ALL)/T-cell lymphoblastic lymphoma (T-LBL) treatment trial.
- The most common adverse reactions in pediatric patients, regardless of causality, were hematologic disorders (anemia, leukopenia, neutropenia, and thrombocytopenia). Of the non-hematologic adverse reactions in pediatric patients, the most frequent adverse reactions reported were headache, increased transaminase levels, decreased blood potassium, decreased blood albumin, increased blood bilirubin, and vomiting.
- The most common adverse reactions in pediatric patients, by System Organ Class, regardless of causality, including severe or life threatening adverse reactions (NCI Common Toxicity Criteria Grade 3 or Grade 4) and fatal adverse reactions (Grade 5) are shown in Table 3.
- Neurologic Adverse Reactions: Nervous system adverse reactions, regardless of drug relationship, were reported for 42% of pediatric patients across the Phase I and Phase II trials. The most common neurologic adverse reactions (≥2%) in pediatric patients, regardless of causality, including all grades (NCI Common Toxicity Criteria) are shown in Table 4.
- The other Grade 3 neurologic adverse reaction in pediatric patients, regardless of causality, was hypertonia reported in 1 patient (1%). The additional Grade 4 neurologic adverse reactions, regardless of causality, were 3rd nerve paralysis, and 6th nerve paralysis, each reported in 1 patient (1%).
- The other neurologic adverse reactions, regardless of causality, reported as Grade 1, 2, or unknown in pediatric patients were dysarthria, encephalopathy, hydrocephalus, hyporeflexia, lethargy, mental impairment, paralysis, and sensory loss, each reported in 1 patient (1%).
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of ARRANON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Infections and Infestations: Fatal opportunistic infections.
- Metabolism and Nutrition Disorders: Tumor lysis syndrome.
- Nervous System Disorders: Demyelination and ascending peripheral neuropathies similar in appearance to Guillain-Barré syndrome.
- Musculoskeletal and Connective Disorders: Rhabdomyolysis, blood creatine phosphokinase increased.
# Drug Interactions
- Administration of nelarabine in combination with adenosine deaminase inhibitors, such as pentostatin, is not recommended.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- ARRANON can cause fetal harm when administered to a pregnant woman. Nelarabine administered to rabbits during the period of organogenesis caused increased incidences of fetal malformations, anomalies, and variations at doses ≥360 mg/m2/day (8-hour IV infusion; approximately ¼ the adult dose compared on a mg/m2 basis), which was the lowest dose tested. Cleft palate was seen in rabbits given 3,400 mg/m2/day (approximately 2-fold the adult dose), absent pollices (digits) in rabbits given ≥1,200 mg/m2/day (approximately ¾ the adult dose), while absent gall bladder, absent accessory lung lobes, fused or extra sternebrae, and delayed ossification was seen at all doses. Maternal body weight gain and fetal body weights were reduced in rabbits given 3,400 mg/m2/day (approximately 2-fold the adult dose), but could not account for the increased incidence of malformations seen at this or lower administered doses.
- There are no adequate and well-controlled studies of ARRANON in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with ARRANON.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nelarabine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Nelarabine during labor and delivery.
### Nursing Mothers
- It is not known whether nelarabine or ara-G are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ARRANON, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of ARRANON has been established in pediatric patients.
### Geriatic Use
- Clinical studies of ARRANON did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In an exploratory analysis, increasing age, especially age 65 years and older, appeared to be associated with increased rates of neurologic adverse reactions. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
- There is no FDA guidance on the use of Nelarabine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Nelarabine with respect to specific racial populations.
### Renal Impairment
- Ara-G clearance decreased as renal function decreased. Because the risk of adverse reactions to this drug may be greater in patients with moderate (CLcr 30 to 50 mL/min) or severe (CLcr <30 mL/min) renal impairment, these patients should be closely monitored for toxicities when treated with ARRANON.
### Hepatic Impairment
- The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated. Because the risk of adverse reactions to this drug may be greater in patients with severe hepatic impairment (total bilirubin >3 times upper limit of normal), these patients should be closely monitored for toxicities when treated with ARRANON.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Nelarabine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Nelarabine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Recommended Dosage
- This product is for intravenous use only.
- The recommended duration of treatment for adult and pediatric patients has not been clearly established. In clinical trials, treatment was generally continued until there was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment.
- Adult Dosage: The recommended adult dose of ARRANON is 1,500 mg/m² administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. ARRANON is administered undiluted.
- Pediatric Dosage: The recommended pediatric dose of ARRANON is 650 mg/m² administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days. ARRANON is administered undiluted.
Dosage Modification
- Administration of ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater. Dosage may be delayed for other toxicity including hematologic toxicity.
Adjustment of Dose in Special Populations
- ARRANON has not been studied in patients with renal or hepatic dysfunction. No dose adjustment is recommended for patients with a creatinine clearance (CLcr) ≥50 mL/min. There are insufficient data to support a dose recommendation for patients with a CLcr <50 mL/min.
Prevention of Hyperuricemia
- Appropriate measures (e.g., hydration, urinealkalinization, and prophylaxis with allopurinol) must be taken to prevent hyperuricemia.
Instructions for Handling, Preparation, and Administration
- Handling: ARRANON is a cytotoxic agent. Caution should be used during handling and preparation. Use of gloves and other protective clothing to prevent skin contact is recommended. Proper aseptic technique should be used. Guidelines for proper handling and disposal of anticancer drugs have been published.
- Preparation and Administration: Do not dilute ARRANON prior to administration. The appropriate dose of ARRANON is transferred into polyvinylchloride (PVC) infusion bags or glass containers and administered as a 2-hour infusion in adult patients and as a 1-hour infusion in pediatric patients.
- Prior to administration, inspect the drug product visually for particulate matter and discoloration.
- Stability: ARRANON Injection is stable in polyvinylchloride (PVC) infusion bags and glass containers for up to 8 hours at up to 30° C.
DOSAGE FORMS AND STRENGTHS
- 250 mg/50 mL (5 mg/mL) vial
### Monitoring
- Severe neurologic adverse reactions have been reported with the use of ARRANON®. Close monitoring for neurologic adverse reactions is strongly recommended, and ARRANON should be discontinued for neurologic adverse reactions of NCI Common Toxicity Criteria Grade 2 or greater.
- Complete blood counts including platelets should be monitored regularly for hematologic reactions.
- Closely monitor patients with moderate or severe renal impairment for toxicities.
- Closely monitor patients with severe hepatic impairment for toxicities.
# IV Compatibility
- There is limited information regarding IV Compatibility of Nelarabine in the drug label.
# Overdosage
- There is no known antidote for overdoses of ARRANON. It is anticipated that overdosage would result in severe neurotoxicity (possibly including paralysis, coma), myelosuppression, and potentially death. In the event of overdose, supportive care consistent with good clinical practice should be provided.
- Nelarabine has been administered in clinical trials up to a dose of 2,900 mg/m2 on Days 1, 3, and 5 to 2 adult patients. At a dose of 2,200 mg/m2 given on Days 1, 3, and 5 every 21 days, 2 patients developed a significant Grade 3 ascending sensory neuropathy. MRI evaluations of the 2 patients demonstrated findings consistent with a demyelinating process in the cervical spine.
# Pharmacology
## Mechanism of Action
Nelarabine is a prodrug of the deoxyguanosine analogue 9-β-D-arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the active 5’-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA synthesis and cell death. Other mechanisms may contribute to the cytotoxic and systemic toxicity of nelarabine.
## Structure
- ARRANON (nelarabine) is a prodrug of the cytotoxic deoxyguanosine analogue, 9-β-D-arabinofuranosylguanine (ara-G).
- The chemical name for nelarabine is 2-amino-9-β-D-arabinofuranosyl-6-methoxy-9H-purine. It has the molecular formula C11H15N5O5 and a molecular weight of 297.27. Nelarabine has the following structural formula:
- Nelarabine is slightly soluble to soluble in water and melts with decomposition between 209° and 217° C.
- ARRANON Injection is supplied as a clear, colorless, sterile solution in glass vials. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. ARRANON is intended for intravenous infusion.
- Hydrochloric acid and sodium hydroxide may have been used to adjust the pH. The solution pH ranges from 5.0 to 7.0.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Nelarabine in the drug label.
## Pharmacokinetics
- Absorption: Following intravenous administration of nelarabine to adult patients with refractory leukemia or lymphoma, plasma ara-G Cmax values generally occurred at the end of the nelarabine infusion and were generally higher than nelarabine Cmax values, suggesting rapid and extensive conversion of nelarabine to ara-G. Mean plasma nelarabine and ara-G Cmax values were 5.0 ± 3.0 mcg/mL and 31.4 ± 5.6 mcg/mL, respectively, after a 1,500 mg/m2 nelarabine dose infused over 2 hours in adult patients. The area under the concentration-time curve (AUC) of ara-G is 37 times higher than that for nelarabine on Day 1 after nelarabine IV infusion of 1,500 mg/m2 dose (162 ± 49 mcg.h/mL versus 4.4 ± 2.2 mcg.h/mL, respectively). Comparable Cmax and AUC values were obtained for nelarabine between Days 1 and 5 at the nelarabine adult dosage of 1,500 mg/m2, indicating that nelarabine does not accumulate after multiple-dosing. There are not enough ara-G data to make a comparison between Day 1 and Day 5. After a nelarabine adult dose of 1,500 mg/m2, intracellular Cmax for ara-GTP appeared within 3 to 25 hours on Day 1. Exposure (AUC) to intracellular ara-GTP was 532 times higher than that for nelarabine and 14 times higher than that for ara-G (2,339 ± 2,628 mcg.h/mL versus 4.4 ± 2.2 mcg.h/mL and 162 ± 49 mcg.h/mL, respectively). Because the intracellular levels of ara-GTP were so prolonged, its elimination half-life could not be accurately estimated.
- Distribution: Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, VSS values were 197 ± 216 L/m2 in adult patients. For ara-G, VSS/F values were 50 ± 24 L/m2 in adult patients.
- Nelarabine and ara-G are not substantially bound to human plasma proteins (<25%) in vitro, and binding is independent of nelarabine or ara-G concentrations up to 400 μM.
- Metabolism: The principal route of metabolism for nelarabine is O-demethylation by adenosine deaminase to form ara-G, which undergoes hydrolysis to form guanine. In addition, some nelarabine is hydrolyzed to form methylguanine, which is O-demethylated to form guanine. Guanine is N-deaminated to form xanthine, which is further oxidized to yield uric acid.
- Excretion: Nelarabine and ara-G are partially eliminated by the kidneys. Mean urinary excretion of nelarabine and ara-G was 6.6 ± 4.7% and 27 ± 15% of the administered dose, respectively, in 28 adult patients over the 24 hours after nelarabine infusion on Day 1. Renal clearance averaged 24 ± 23 L/h for nelarabine and 6.2 ± 5.0 L/h for ara-G in 21 adult patients. Combined Phase I pharmacokinetic data at nelarabine doses of 199 to 2,900 mg/m2 (n = 66 adult patients) indicate that the mean clearance (CL) of nelarabine is 197 ± 189 L/h/m2 on Day 1. The apparent clearance of ara-G (CL/F) is 10.5 ± 4.5 L/h/m2 on Day 1. Nelarabine and ara-G are rapidly eliminated from plasma with a mean half-life of 18 minutes and 3.2 hours, respectively, in adult patients.
- Pediatrics: No pharmacokinetic data are available in pediatric patients at the once-daily 650 mg/m2 nelarabine dosage. Combined Phase I pharmacokinetic data at nelarabine doses of 104 to 2,900 mg/m2 indicate that the mean clearance (CL) of nelarabine is about 30% higher in pediatric patients than in adult patients (259 ± 409 L/h/m2 versus 197 ± 189 L/h/m2, respectively) (n = 66 adults, n = 22 pediatric patients) on Day 1. The apparent clearance of ara-G (CL/F) is comparable between the two groups (10.5 ± 4.5 L/h/m2 in adult patients and 11.3 ± 4.2 L/h/m2 in pediatric patients) on Day 1. Nelarabine and ara-G are extensively distributed throughout the body. For nelarabine, VSS values were 213 ± 358 L/m2 in pediatric patients. For ara-G, VSS/F values were 33 ± 9.3 L/m2 in pediatric patients. Nelarabine and ara-G are rapidly eliminated from plasma in pediatric patients, with a half-life of 13 minutes and 2 hours, respectively.
- Effect of Age: Age has no effect on the pharmacokinetics of nelarabine or ara-G in adults. Decreased renal function, which is more common in the elderly, may reduce ara-G clearance.
- Effect of Gender: Gender has no effect on nelarabine or ara-G pharmacokinetics.
- Effect of Race: In general, nelarabine mean clearance and volume of distribution values tend to be higher in whites (n = 63) than in blacks (by about 10%) (n = 15). The opposite is true for ara-G; mean apparent clearance and volume of distribution values tend to be lower in whites than in blacks (by about 15% to 20%). No differences in safety or effectiveness were observed between these groups.
- Effect of Renal Impairment: The pharmacokinetics of nelarabine and ara-G have not been specifically studied in renally impaired or hemodialyzed patients. Nelarabine is excreted by the kidney to a small extent (5% to 10% of the administered dose). Ara-G is excreted by the kidney to a greater extent (20% to 30% of the administered nelarabine dose). In the combined Phase I trials, patients were categorized into 3 groups: normal with CLcr >80 mL/min (n = 67), mild with CLcr = 50 to 80 mL/min (n = 15), and moderate with CLcr <50 mL/min (n = 3). The mean apparent clearance (CL/F) of ara-G was about 15% and 40% lower in patients with mild and moderate renal impairment, respectively, than in patients with normal renal function. No differences in safety or effectiveness were observed.
- Effect of Hepatic Impairment: The influence of hepatic impairment on the pharmacokinetics of nelarabine has not been evaluated.
- Drug Interactions: Cytochrome P450: Nelarabine and ara-G did not significantly inhibit the activities of the human hepatic cytochrome P450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at concentrations of nelarabine and ara-G up to 100 μM.
- Fludarabine: Administration of fludarabine 30 mg/m2 as a 30-minute infusion 4 hours before a 1,200-mg/m2 infusion of nelarabine did not affect the pharmacokinetics of nelarabine, ara-G, or ara-GTP in 12 patients with refractory leukemia.
Pentostatin: There is in vitro evidence that pentostatin is a strong inhibitor of adenosine deaminase. Inhibition of adenosine deaminase may result in a reduction in the conversion of the prodrug nelarabine to its active moiety and consequently in a reduction in efficacy of nelarabine and/or change in adverse reaction profile of either drug.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Carcinogenicity testing of nelarabine has not been done. However, nelarabine was mutagenic when tested in vitro in L5178Y/TK mouse lymphoma cells with and without metabolic activation. No studies have been conducted in animals to assess genotoxic potential or effects on fertility. The effect on human fertility is unknown.
# Clinical Studies
- The safety and efficacy of ARRANON were evaluated in two open-label, single-arm, multicenter trials.
Adult Clinical Trial
- The safety and efficacy of ARRANON in adult patients were studied in a clinical trial which included 39 treated patients, 28 who had T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL) that had relapsed following or was refractory to at least two prior induction regimens. A 1,500-mg/m2 dose of ARRANON was administered intravenously over 2 hours on Days 1, 3, and 5 repeated every 21 days. Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with ARRANON. Seventeen patients had a diagnosis of T-ALL and 11 had a diagnosis of T-LBL. For patients with ≥2 prior inductions, the age range was 16 to 65 years (mean 34 years) and most patients were male (82%) and Caucasian (61%). Patients with central nervous system (CNS) disease were not eligible.
- Complete response (CR) in this trial was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without complete hematologic recovery (CR*) was also assessed. The results of the trial for patients who had received ≥2 prior inductions are shown in Table 5.
- The mean number of days on therapy was 56 days (range of 10 to 136 days). Time to CR plus CR* ranged from 2.9 to 11.7 weeks.
Pediatric Clinical Trial
- The safety and efficacy of ARRANON in pediatric patients were studied in a clinical trial which included patients aged 21 years and younger, who had relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LBL). Eighty-four (84) patients, 39 of whom had received two or more prior induction regimens, were treated with 650 mg/m2/day of ARRANON administered intravenously over 1 hour daily for 5 consecutive days repeated every 21 days (see Table 6). Patients who experienced signs or symptoms of Grade 2 or greater neurologic toxicity on therapy were to be discontinued from further therapy with ARRANON.
- The 84 patients ranged in age from 2.5 to 21.7 years (overall mean: 11.9 years), 52% were 3 to 12 years of age and most were male (74%) and Caucasian (62%). The majority (77%) of patients had a diagnosis of T-ALL.
- Complete response (CR) in this trial was defined as bone marrow blast counts ≤5%, no other evidence of disease, and full recovery of peripheral blood counts. Complete response without full hematologic recovery (CR*) was also assessed as a meaningful outcome in this heavily pretreated population. Duration of response is reported from date of response to date of relapse, and may include subsequent stem cell transplant. Efficacy results are presented in Table 7.
- The mean number of days on therapy was 46 days (range: 7 to 129 days). Median time to CR plus CR* was 3.4 weeks (95% CI: 3.0, 3.7).
# How Supplied
- ARRANON Injection is supplied as a clear, colorless, sterile solution in Type I, clear glass vials with a gray bromobutyl rubber stopper (not made with natural rubber latex) and a red snap-off aluminum seal. Each vial contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP. Vials (NDC 0007-4401-01) are available in the following carton size:
- NDC 0007-4401-06 (package of 6)
## Storage
- Store at 25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patient labeling is provided as a tear-off leaflet at the end of this full prescribing information. However, inform the patients of the following:
- Since patients receiving nelarabine therapy may experience somnolence, they should be cautioned about operating hazardous machinery, including automobiles.
- Patients should be instructed to contact their physician if they experience new or worsening symptoms of peripheral neuropathy. These signs and symptoms include: tingling or numbness in fingers, hands, toes, or feet; difficulty with the fine motor coordination tasks such as buttoning clothing; unsteadiness while walking; weakness arising from a low chair; weakness in climbing stairs; increased tripping while walking over uneven surfaces.
- Patients should be instructed that seizures have been known to occur in patients who receive nelarabine. If a seizure occurs, the physician administering ARRANON should be promptly informed.
- Patients who develop fever or signs of infection while on therapy should notify their physician promptly.
- Patients should be advised to use effective contraceptive measures to prevent pregnancy and to avoid breastfeeding during treatment with ARRANON.
# Precautions with Alcohol
- Alcohol-Nelarabine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Arranon
# Look-Alike Drug Names
- A® — B®[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/506U78 | |
b867c53d0d2cf6aab777eee767c2a486477e65a2 | wikidoc | AA battery | AA battery
For the military weapon, see Anti-Aircraft
An AA battery (Template:Pronounced or Template:IPA) is a dry cell-type battery commonly used in portable electronic devices. The AA battery type was standardized by ANSI in 1947 and is also known internationally as LR6 (alkaline), FR6 (lithium-ion), R6 (carbon-zinc) or Mignon. As an AA battery is composed of a single chamber, it is more correctly referred to as a cell. Technically, a battery is a collection of cells working together, such as in a car battery. This article nonetheless prefers the more common term "battery".
An AA battery measures 51 mm in length (50.1 mm without the button terminal), 13.5–14.5 mm in diameter, (1.97×0.56 inches). Traditional alkaline AA batteries weigh roughly 23 g (0.81 ounces), Lithium AA batteries weigh around 15 g (0.5 oz), and rechargeable NiMH batteries weigh about 31 g (1.1 oz).
The nominal output voltage of single-use AA batteries is 1.5 volts, while NiCd and NiMH rechargeable batteries have a nominal voltage of 1.2 V. Specialty batteries based on more unusual chemistries can run at a voltage as high as 1.6 V under load. The voltage of an AA battery is the same as an AAA battery, C cell or D cell. AA batteries, however, provide power for a longer period than AAA batteries, because their larger size allows them to store a greater mass of anode material which is consumed as it does electrical work. C and D cells, being larger, last longer still; as a rough guide, the capacity of a battery scales linearly with its mass.
Primary (non-rechargeable) zinc-carbon AA batteries of 400–900 milliamp-hours capacity are commonly made using Leclanché cell technology. Zinc-chloride batteries of 1000 to 1500 mAh are often sold as "long life" or "heavy duty". Alkaline batteries from 1700 mAh to almost 3000 mAh cost a little more, but last proportionally longer.
Single-use lithium batteries are also available for high demand devices such as digital cameras, where their high cost is offset by longer running time between battery changes. As of 2008, the only 1.5 V lithium AA is manufactured by Energizer, although AA-sized batteries with different nominal voltages are available from others. These should only be used in devices rated for the higher voltage.
# Rechargeable AA batteries
The capacity of rechargeable AA batteries varies with the technology used. Nickel-cadmium (NiCd or NiCad) AAs with a capacity of 650 to 800 mAh are commonly available, while 800 to 1000 mAh AA types are rarer and more expensive. Nickel-metal hydride (NiMH) AAs are also available in various capacities ranging from 1300 to 2850 mAh.
The older NiCd battery chemistry can supply a higher current than typical NiMHs, so NiCds are commonly used to power model cars or other relatively high-current-draw devices. New NiMH AAs designed for high current applications are beginning to become available. These use different construction and have lower capacity (1400–1600 mAh) than the highest capacity NiMH batteries. A newer form, low self-discharge NiMH batteries, are sold precharged and ready for use.
Rechargeable AA-sized batteries based on Li-ion chemistry have also been introduced. These batteries do not supply voltage in the 1.2–1.5 V range and are thus not compatible with most AA-based devices. Recent developments include AA Batteries with embedded functionality such as a built-in charger and USB connector within the AA format USBCELL, enabling the battery to be charged by plugging into a USB port without a charger .
# The insides of a ZnC battery
The common zinc-carbon or zinc-chloride AA battery consists of a graphite rod in the center forming an electrode, an anode/electrolyte mix consisting mainly of manganese oxide, a zinc outer shell which serves as the cathode, and a paper, plastic or steel cover. See Zinc-carbon battery. There is sometimes a pressure valve at the bottom to prevent explosions. However, the pressure valves generally will not prevent leakage or catastrophic failure of the shell if the battery is exposed to fire or extreme heat.
If a Zn-C or Zn-Cl battery is discharged too far, corrosion of the cathode, which is the zinc shell, can occur. If this becomes corroded enough, a breach in the shell can allow electrolyte to leak out. This is a common cause of damage to battery-powered appliances which are left unattended for long periods with batteries inside. The electrolyte can also cause minor skin damage, and should be kept away from eyes, and not ingested.
# Inside an alkaline battery
More common today than the lower cost ZnC batteries are alkaline cells. Different variants exist, offering roughly double to three times the capacity of ZnC cells. Rather than zinc chloride as the electrolyte, potassium hydroxide is used. | AA battery
Template:Expand
For the military weapon, see Anti-Aircraft
An AA battery (Template:Pronounced or Template:IPA) is a dry cell-type battery commonly used in portable electronic devices. The AA battery type was standardized by ANSI in 1947 and is also known internationally as LR6 (alkaline), FR6 (lithium-ion), R6 (carbon-zinc) or Mignon. As an AA battery is composed of a single chamber, it is more correctly referred to as a cell. Technically, a battery is a collection of cells working together, such as in a car battery. This article nonetheless prefers the more common term "battery".
An AA battery measures 51 mm in length (50.1 mm without the button terminal), 13.5–14.5 mm in diameter,[1] (1.97×0.56 inches). Traditional alkaline AA batteries weigh roughly 23 g (0.81 ounces), Lithium AA batteries weigh around 15 g (0.5 oz), and rechargeable NiMH batteries weigh about 31 g (1.1 oz).
The nominal output voltage of single-use AA batteries is 1.5 volts, while NiCd and NiMH rechargeable batteries have a nominal voltage of 1.2 V. Specialty batteries based on more unusual chemistries can run at a voltage as high as 1.6 V under load.[2] The voltage of an AA battery is the same as an AAA battery, C cell or D cell. AA batteries, however, provide power for a longer period than AAA batteries, because their larger size allows them to store a greater mass of anode material which is consumed as it does electrical work. C and D cells, being larger, last longer still; as a rough guide, the capacity of a battery scales linearly with its mass.
Primary (non-rechargeable) zinc-carbon AA batteries of 400–900 milliamp-hours capacity are commonly made using Leclanché cell technology. Zinc-chloride batteries of 1000 to 1500 mAh are often sold as "long life" or "heavy duty". Alkaline batteries from 1700 mAh to almost 3000 mAh cost a little more, but last proportionally longer.
Single-use lithium batteries are also available for high demand devices such as digital cameras, where their high cost is offset by longer running time between battery changes. As of 2008, the only 1.5 V lithium AA is manufactured by Energizer[1], although AA-sized batteries with different nominal voltages are available from others. These should only be used in devices rated for the higher voltage.
# Rechargeable AA batteries
The capacity of rechargeable AA batteries varies with the technology used. Nickel-cadmium (NiCd or NiCad) AAs with a capacity of 650 to 800 mAh are commonly available, while 800 to 1000 mAh AA types are rarer and more expensive. Nickel-metal hydride (NiMH) AAs are also available in various capacities ranging from 1300 to 2850 mAh.
The older NiCd battery chemistry can supply a higher current than typical NiMHs, so NiCds are commonly used to power model cars or other relatively high-current-draw devices. New NiMH AAs designed for high current applications are beginning to become available. These use different construction and have lower capacity (1400–1600 mAh) than the highest capacity NiMH batteries. A newer form, low self-discharge NiMH batteries, are sold precharged and ready for use.
Rechargeable AA-sized batteries based on Li-ion chemistry have also been introduced. These batteries do not supply voltage in the 1.2–1.5 V range and are thus not compatible with most AA-based devices. Recent developments include AA Batteries with embedded functionality such as a built-in charger and USB connector within the AA format USBCELL, enabling the battery to be charged by plugging into a USB port without a charger [2].
# The insides of a ZnC battery
The common zinc-carbon or zinc-chloride AA battery consists of a graphite rod in the center forming an electrode, an anode/electrolyte mix consisting mainly of manganese oxide, a zinc outer shell which serves as the cathode, and a paper, plastic or steel cover. See Zinc-carbon battery. There is sometimes a pressure valve at the bottom to prevent explosions. However, the pressure valves generally will not prevent leakage or catastrophic failure of the shell if the battery is exposed to fire or extreme heat.
If a Zn-C or Zn-Cl battery is discharged too far, corrosion of the cathode, which is the zinc shell, can occur. If this becomes corroded enough, a breach in the shell can allow electrolyte to leak out. This is a common cause of damage to battery-powered appliances which are left unattended for long periods with batteries inside. The electrolyte can also cause minor skin damage, and should be kept away from eyes, and not ingested.
# Inside an alkaline battery
More common today than the lower cost ZnC batteries are alkaline cells. Different variants exist, offering roughly double to three times the capacity of ZnC cells. Rather than zinc chloride as the electrolyte, potassium hydroxide is used. | https://www.wikidoc.org/index.php/AA_battery | |
2ea3d53e3e5941a787e33ce77c082ea7310efb9a | wikidoc | Paclitaxel | Paclitaxel
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Paclitaxel is a mitotic inhibitor that is FDA approved for the treatment of metastatic breast cancer, non-small cell lung cancer and adenocarcinoma of the pancreas. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, diarrhea, inflammatory disease of mucous membrane, nausea and vomiting, any grade of anemia, leukopenia, any grade of neutropenia, any grade of thrombocytopenia, any grade of hypersensitivity reaction, arthralgia, myalgia and peripheral neuropathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Breast Cancer
- Paclitaxel is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
- Dosage: 260 mg/m2 administered intravenously over 30 minutes every 3 weeks
### Non-Small Cell Lung Cancer
- Paclitaxel is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
- Dosage: 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle.
- Administer carboplatin on Day 1 of each 21 day cycle immediately after paclitaxel
### Adenocarcinoma of the Pancreas
- Paclitaxel is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.
- Dosage: 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle.
- Administer gemcitabine immediately after paclitaxel on Days 1, 8 and 15 of each 28-day cycle
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paclitaxel in adult patients.
### Non–Guideline-Supported Use
- Angiosarcoma
- Breast cancer
- Cancer of unknown origin
- Carcinoma of bladder
- Carcinoma of esophagus
- In combination with carboplatin or cisplatin in carcinoma of fallopian tube
- Carcinoma of prostate
- Cervical cancer
- Gastric cancer
- Head and neck cancer
- Malignant lymphoma
- Malignant neoplasm of endometrium of corpus uteri
- Malignant tumor of nasopharynx
- In combination with carboplatin or cisplatin in malignant tumor of peritoneum
- Multiple myeloma of ovarian origin
- Non-small cell lung cancer
- Non-small cell lung cancer, First-line treatment in combination with bevacizumab and carboplatin for advanced/metastatic non-squamous cell disease
- Oligodendroglioma of brain
- Ovarian cancer
- Small cell carcinoma of lung
- Testicular cancer
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Paclitaxel FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paclitaxel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Paclitaxel in pediatric patients.
# Contraindications
- Paclitaxel should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
- Patients who experience a severe hypersensitivity reaction to paclitaxel should not be rechallenged with the drug.
# Warnings
### Hematologic Effects
- Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of paclitaxel.
- In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.
- Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer).
- Do not administer paclitaxel to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of paclitaxel therapy, reduce the dose of paclitaxel in subsequent courses in patients with either MBC or NSCLC.
- In patients with MBC, resume treatment with every-3-week cycles of paclitaxel after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
- In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly paclitaxel and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle.
- In patients with adenocarcinoma of the pancreas, withhold paclitaxel and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended.
### Nervous System
- Sensory neuropathy is dose- and schedule-dependent.
- The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification.
- If ≥ Grade 3 sensory neuropathy develops, withhold paclitaxel treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of paclitaxel
### Sepsis
- Sepsis occurred in 5% of patients with or without neutropenia who received paclitaxel in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis.
- If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics.
- For febrile neutropenia, interrupt paclitaxel and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels.
### Pneumonitis
- Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving paclitaxel in combination with gemcitabine.
- Monitor patients for signs and symptoms of pneumonitis and interrupt paclitaxel and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with paclitaxel and gemcitabine.
### Hypersensitivity
- Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to paclitaxel should not be re-challenged with this drug.
### Albumin (Human)
- Paclitaxel contains albumin (human). Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases
- A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.
- No cases of transmission of viral diseases or CJD have ever been identified for albumin.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions (≥ 20%) with single-agent use of paclitaxel in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.
- The most common adverse reactions (≥ 20%) of paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue.
- The most common serious adverse reactions of paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%).
- The most common adverse reactions resulting in permanent discontinuation of paclitaxel are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%).
- The most common adverse reactions resulting in dose reduction of paclitaxel are neutropenia (24%), thrombocytopenia (13%), and anemia (6%).
- The most common adverse reactions leading to withholding or delay in paclitaxel dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
- In a randomized open-label trial of paclitaxel in combination with gemcitabine for pancreatic adenocarcinoma, the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of paclitaxel are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.
- The most common serious adverse reactions of paclitaxel (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%).
- The most common adverse reactions resulting in permanent discontinuation of paclitaxel are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%).
- The most common adverse reactions resulting in dose reduction of paclitaxel are neutropenia (10%) and peripheral neuropathy (6%).
- The most common adverse reactions leading to withholding or delay in paclitaxel dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).
## Postmarketing Experience
### Hypersensitivity Reactions
- Severe and sometimes fatal hypersensitivity reactions have been reported with paclitaxel. The use of paclitxel in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
### Cardiovascular
- There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with paclitaxel.
- Most of the individuals were previously exposed to cardiotoxic drugs ,such as anthracyclines, or had underlying cardiac history.
### Respiratory
- There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving paclitaxel and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.
- Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with paclitaxel.
### Neurologic
- Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.
### Vision Disorders
- Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage.
- Reduced visual acuity due to cystoid macular edema (CME)
- After cessation of treatment, CME improves and visual acuity may return to baseline.
### Hepatic
- Reports of hepatic necrosis and hepatic encephalopathy leading to death
### Gastrointestinal
- Intestinal obstruction
- Intestinal perforation
- Pancreatitis
- Ischemic colitis
- Neutropenic enterocolitis (typhlitis)
### Injection Site Reaction
- Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety.
- In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days.
- Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
### Other Clinical Events
- Skin reactions including generalized or maculopapular rash, erythema, and pruritus.
- Photosensitivity reactions
- Radiation recall phenomenon
- In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia
- Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported
- Conjunctivitis
- Cellulitis
- Increased lacrimation
# Drug Interactions
- The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4.
- Caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies in pregnant women using paclitaxel. Based on its mechanism of action and findings in animals, paclitaxel can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving paclitaxel.
- Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paclitaxel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Paclitaxel during labor and delivery.
### Nursing Mothers
- It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of paclitaxel in pediatric patients have not been evaluated.
### Geriatic Use
- Of the 229 patients in the randomized study who received paclitaxel for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received paclitaxel.
- Of the 514 patients in the randomized study who received paclitaxel and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.
- Of the 431 patients in the randomized study who received paclitaxel and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of paclitaxel did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Paclitaxel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Paclitaxel with respect to specific racial populations.
### Renal Impairment
Adjustment of the starting paclitaxel dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥30 to <90 mL/min).
There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min).
### Hepatic Impairment
- Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of paclitaxel in patients with hepatic impairment should be performed with caution.
- Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.
- Paclitaxel is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, paclitaxel is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic impairment.
### Females of Reproductive Potential and Males
- Men should be advised not to father a child while receiving paclitaxel.
- Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females.
### Immunocompromised Patients
There is no FDA guidance one the use of Paclitaxel in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Paclitaxel Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Paclitaxel and IV administrations.
# Overdosage
There is no known antidote for paclitaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.
# Pharmacology
## Mechanism of Action
Paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
## Structure
The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.91.
## Pharmacodynamics
There is limited information regarding Paclitaxel Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
- The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of paclitaxel at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination.
- The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the pharmacokinetics of paclitaxel for paclitaxel were independent of the duration of intravenous administration.
### Distribution
- Paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.
### Metabolism
- In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.
### Elimination
- At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.
- After a 30-minute infusion of 260 mg/m2 doses of paclitaxel, the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.
- Fecal excretion was approximately 20% of the total dose administered.
## Nonclinical Toxicology
- The carcinogenic potential of paclitaxel has not been studied.
- Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice).
- Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females.
- A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis).
- Testicular atrophy/degeneration was observed in single-dose toxicology studies in rodents administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m2 in rodents and 175 mg/m2 in dogs.
# Clinical Studies
### Metastatic Breast Cancer
- Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of paclitaxel in metastatic breast cancer.
- In one study, paclitaxel was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m2 as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.
- This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive paclitaxel at a dose of 260 mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.
- In this trial, patients in the paclitaxel treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. There was no statistically significant difference in overall survival between the two study arms.
### Non-Small Cell Lung Cancer
- A multicenter, randomized, open-label study was conducted in 1052 chemonaive patients with Stage IIIb/IV non-small cell lung cancer to compare ABRAXANE in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mgmin/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. Treatment was administered until disease progression or development of an unacceptable toxicity. The major efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).
- In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1, and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both study arms.
- Patients in the ABRAXANE/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm (33% versus 25%). There was no statistically significant difference in overall survival between the two study arms.
### Adenocarcinoma of the Pancreas
- A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing ABRAXANE plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung disease. Patients with rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day screening period prior to study randomization were ineligible.
- A total of 861 patients were randomized (1:1) to the ABRAXANE/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE 125 mg/m2 as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m2 as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized to gemcitabine received 1000 mg/m2 as an intravenous infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m2 on Days 1, 8 and 15 of each subsequent 28-day cycle. Patients in both arms received treatment until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).
- In the intent to treat (all randomized) population, the median age was 63 years (range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%).
- In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects, the treatment effects on overall survival were similar to that observed in the overall study population.
# How Supplied
100 mg of paclitaxel in a single-use vial
- Individually packaged in a carton.
- NDC No.: 68817-134-50
## Storage
At 20°C to 25°C (68°F to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Paclitaxel injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving paclitaxel.
- Advise men not to father a child while receiving paclitaxel.
- Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection.
- Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.
- Patients must be informed that sensory neuropathy occurs frequently with paclitaxel and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities.
- Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with paclitaxel.
- Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal.
- Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath.
# Precautions with Alcohol
Alcohol-Paclitaxel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Taxol
- Onxol
- Nov-Onxol
- Paclitaxel Novaplus
- Abraxane
# Look-Alike Drug Names
There is limited information regarding Paclitaxel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Paclitaxel
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2];Aparna Vuppala, M.B.B.S. [3]
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# Black Box Warning
# Overview
Paclitaxel is a mitotic inhibitor that is FDA approved for the treatment of metastatic breast cancer, non-small cell lung cancer and adenocarcinoma of the pancreas. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, diarrhea, inflammatory disease of mucous membrane, nausea and vomiting, any grade of anemia, leukopenia, any grade of neutropenia, any grade of thrombocytopenia, any grade of hypersensitivity reaction, arthralgia, myalgia and peripheral neuropathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Metastatic Breast Cancer
- Paclitaxel is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
- Dosage: 260 mg/m2 administered intravenously over 30 minutes every 3 weeks
### Non-Small Cell Lung Cancer
- Paclitaxel is indicated for the first-line treatment of locally advanced or metastatic non-small cell lung cancer, in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy.
- Dosage: 100 mg/m2 administered as an intravenous infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle.
- Administer carboplatin on Day 1 of each 21 day cycle immediately after paclitaxel
### Adenocarcinoma of the Pancreas
- Paclitaxel is indicated for the first-line treatment of patients with metastatic adenocarcinoma of the pancreas, in combination with gemcitabine.
- Dosage: 125 mg/m2 administered as an intravenous infusion over 30-40 minutes on Days 1, 8 and 15 of each 28-day cycle.
- Administer gemcitabine immediately after paclitaxel on Days 1, 8 and 15 of each 28-day cycle
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paclitaxel in adult patients.
### Non–Guideline-Supported Use
- Angiosarcoma
- Breast cancer
- Cancer of unknown origin
- Carcinoma of bladder
- Carcinoma of esophagus
- In combination with carboplatin or cisplatin in carcinoma of fallopian tube
- Carcinoma of prostate
- Cervical cancer
- Gastric cancer
- Head and neck cancer
- Malignant lymphoma
- Malignant neoplasm of endometrium of corpus uteri
- Malignant tumor of nasopharynx
- In combination with carboplatin or cisplatin in malignant tumor of peritoneum
- Multiple myeloma of ovarian origin
- Non-small cell lung cancer
- Non-small cell lung cancer, First-line treatment in combination with bevacizumab and carboplatin for advanced/metastatic non-squamous cell disease
- Oligodendroglioma of brain
- Ovarian cancer
- Small cell carcinoma of lung
- Testicular cancer
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Paclitaxel FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Paclitaxel in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Paclitaxel in pediatric patients.
# Contraindications
- Paclitaxel should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.
- Patients who experience a severe hypersensitivity reaction to paclitaxel should not be rechallenged with the drug.
# Warnings
### Hematologic Effects
- Bone marrow suppression (primarily neutropenia) is dose-dependent and a dose-limiting toxicity of paclitaxel.
- In clinical studies, Grade 3-4 neutropenia occurred in 34% of patients with metastatic breast cancer (MBC), 47% of patients with non-small cell lung cancer (NSCLC), and 38% of patients with pancreatic cancer.
- Monitor for myelotoxicity by performing complete blood cell counts frequently, including prior to dosing on Day 1 (for MBC) and Days 1, 8, and 15 (for NSCLC and for pancreatic cancer).
- Do not administer paclitaxel to patients with baseline absolute neutrophil counts (ANC) of less than 1,500 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of paclitaxel therapy, reduce the dose of paclitaxel in subsequent courses in patients with either MBC or NSCLC.
- In patients with MBC, resume treatment with every-3-week cycles of paclitaxel after ANC recovers to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.
- In patients with NSCLC, resume treatment if recommended at permanently reduced doses for both weekly paclitaxel and every-3-week carboplatin after ANC recovers to at least 1500 cells/mm3 and platelet count of at least 100,000 cells/mm3 on Day 1 or to an ANC of at least 500 cells/mm3 and platelet count of at least 50,000 cells/mm3 on Days 8 or 15 of the cycle.
- In patients with adenocarcinoma of the pancreas, withhold paclitaxel and gemcitabine if the ANC is less than 500 cells/mm3 or platelets are less than 50,000 cells/mm3 and delay initiation of the next cycle if the ANC is less than 1500 cells/mm3 or platelet count is less than 100,000 cells/mm3 on Day 1 of the cycle. Resume treatment with appropriate dose reduction if recommended.
### Nervous System
- Sensory neuropathy is dose- and schedule-dependent.
- The occurrence of Grade 1 or 2 sensory neuropathy does not generally require dose modification.
- If ≥ Grade 3 sensory neuropathy develops, withhold paclitaxel treatment until resolution to Grade 1 or 2 for metastatic breast cancer or until resolution to ≤ Grade 1 for NSCLC and pancreatic cancer followed by a dose reduction for all subsequent courses of paclitaxel
### Sepsis
- Sepsis occurred in 5% of patients with or without neutropenia who received paclitaxel in combination with gemcitabine. Biliary obstruction or presence of biliary stent were risk factors for severe or fatal sepsis.
- If a patient becomes febrile (regardless of ANC) initiate treatment with broad spectrum antibiotics.
- For febrile neutropenia, interrupt paclitaxel and gemcitabine until fever resolves and ANC ≥ 1500, then resume treatment at reduced dose levels.
### Pneumonitis
- Pneumonitis, including some cases that were fatal, occurred in 4% of patients receiving paclitaxel in combination with gemcitabine.
- Monitor patients for signs and symptoms of pneumonitis and interrupt paclitaxel and gemcitabine during evaluation of suspected pneumonitis. After ruling out infectious etiology and upon making a diagnosis of pneumonitis, permanently discontinue treatment with paclitaxel and gemcitabine.
### Hypersensitivity
- Severe and sometimes fatal hypersensitivity reactions, including anaphylactic reactions, have been reported. Patients who experience a severe hypersensitivity reaction to paclitaxel should not be re-challenged with this drug.
### Albumin (Human)
- Paclitaxel contains albumin (human). Based on effective donor screening and product manufacturing processes, it carries a remote risk for transmission of viral diseases
- A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote.
- No cases of transmission of viral diseases or CJD have ever been identified for albumin.
# Adverse Reactions
## Clinical Trials Experience
- The most common adverse reactions (≥ 20%) with single-agent use of paclitaxel in metastatic breast cancer are alopecia, neutropenia, sensory neuropathy, abnormal ECG, fatigue/asthenia, myalgia/arthralgia, AST elevation, alkaline phosphatase elevation, anemia, nausea, infections, and diarrhea.
- The most common adverse reactions (≥ 20%) of paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia, neutropenia, thrombocytopenia, alopecia, peripheral neuropathy, nausea, and fatigue.
- The most common serious adverse reactions of paclitaxel in combination with carboplatin for non-small cell lung cancer are anemia (4%) and pneumonia (3%).
- The most common adverse reactions resulting in permanent discontinuation of paclitaxel are neutropenia (3%), thrombocytopenia (3%), and peripheral neuropathy (1%).
- The most common adverse reactions resulting in dose reduction of paclitaxel are neutropenia (24%), thrombocytopenia (13%), and anemia (6%).
- The most common adverse reactions leading to withholding or delay in paclitaxel dosing are neutropenia (41%), thrombocytopenia (30%), and anemia (16%).
- In a randomized open-label trial of paclitaxel in combination with gemcitabine for pancreatic adenocarcinoma, the most common (≥ 20%) selected (with a ≥ 5% higher incidence) adverse reactions of paclitaxel are neutropenia, fatigue, peripheral neuropathy, nausea, alopecia, peripheral edema, diarrhea, pyrexia, vomiting, decreased appetite, rash, and dehydration.
- The most common serious adverse reactions of paclitaxel (with a ≥ 1% higher incidence) are pyrexia (6%), dehydration (5%), pneumonia (4%) and vomiting (4%).
- The most common adverse reactions resulting in permanent discontinuation of paclitaxel are peripheral neuropathy (8%), fatigue (4%) and thrombocytopenia (2%).
- The most common adverse reactions resulting in dose reduction of paclitaxel are neutropenia (10%) and peripheral neuropathy (6%).
- The most common adverse reactions leading to withholding or delay in paclitaxel dosing are neutropenia (16%), thrombocytopenia (12%), fatigue (8%), peripheral neuropathy (15%), anemia (5%) and diarrhea (5%).
## Postmarketing Experience
### Hypersensitivity Reactions
- Severe and sometimes fatal hypersensitivity reactions have been reported with paclitaxel. The use of paclitxel in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.
### Cardiovascular
- There have been reports of congestive heart failure, left ventricular dysfunction, and atrioventricular block with paclitaxel.
- Most of the individuals were previously exposed to cardiotoxic drugs ,such as anthracyclines, or had underlying cardiac history.
### Respiratory
- There have been reports of pneumonitis, interstitial pneumonia and pulmonary embolism in patients receiving paclitaxel and reports of radiation pneumonitis in patients receiving concurrent radiotherapy.
- Reports of lung fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety and may also be observed with paclitaxel.
### Neurologic
- Cranial nerve palsies and vocal cord paresis have been reported, as well as autonomic neuropathy resulting in paralytic ileus.
### Vision Disorders
- Reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection suggest persistent optic nerve damage.
- Reduced visual acuity due to cystoid macular edema (CME)
- After cessation of treatment, CME improves and visual acuity may return to baseline.
### Hepatic
- Reports of hepatic necrosis and hepatic encephalopathy leading to death
### Gastrointestinal
- Intestinal obstruction
- Intestinal perforation
- Pancreatitis
- Ischemic colitis
- Neutropenic enterocolitis (typhlitis)
### Injection Site Reaction
- Severe events such as phlebitis, cellulitis, induration, necrosis, and fibrosis have been reported as part of the continuing surveillance of paclitaxel injection safety.
- In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days.
- Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported.
### Other Clinical Events
- Skin reactions including generalized or maculopapular rash, erythema, and pruritus.
- Photosensitivity reactions
- Radiation recall phenomenon
- In some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysesthesia
- Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported
- Conjunctivitis
- Cellulitis
- Increased lacrimation
# Drug Interactions
- The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4.
- Caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit (e.g., ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, and nevirapine) either CYP2C8 or CYP3A4.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- There are no adequate and well-controlled studies in pregnant women using paclitaxel. Based on its mechanism of action and findings in animals, paclitaxel can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving paclitaxel.
- Administration of paclitaxel formulated as albumin-bound particles to rats during pregnancy, on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryofetal toxicities, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Paclitaxel in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Paclitaxel during labor and delivery.
### Nursing Mothers
- It is not known whether paclitaxel is excreted in human milk. Paclitaxel and/or its metabolites were excreted into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of paclitaxel in pediatric patients have not been evaluated.
### Geriatic Use
- Of the 229 patients in the randomized study who received paclitaxel for the treatment of metastatic breast cancer, 13% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among patients who received paclitaxel.
- Of the 514 patients in the randomized study who received paclitaxel and carboplatin for the first-line treatment of non-small cell lung cancer, 31% were 65 years or older and 3.5% were 75 years or older. Myelosuppression, peripheral neuropathy, and arthralgia were more frequent in patients 65 years or older compared to patients younger than 65 years old. No overall difference in effectiveness, as measured by response rates, was observed between patients 65 years or older compared to patients younger than 65 years old.
- Of the 431 patients in the randomized study who received paclitaxel and gemcitabine for the first-line treatment of pancreatic adenocarcinoma, 41% were 65 years or older and 10% were 75 years or older. No overall differences in effectiveness were observed between patients who were 65 years of age or older and younger patients. Diarrhea, decreased appetite, dehydration and epistaxis were more frequent in patients 65 years or older compared with patients younger than 65 years old. Clinical studies of paclitaxel did not include sufficient number of patients with pancreatic cancer who were 75 years and older to determine whether they respond differently from younger patients.
### Gender
There is no FDA guidance on the use of Paclitaxel with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Paclitaxel with respect to specific racial populations.
### Renal Impairment
Adjustment of the starting paclitaxel dose is not required for patients with mild to moderate renal impairment (estimated creatinine clearance ≥30 to <90 mL/min).
There are insufficient data to permit dosage recommendations in patients with severe renal impairment or end stage renal disease (estimated creatinine clearance <30 mL/min).
### Hepatic Impairment
- Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of paclitaxel in patients with hepatic impairment should be performed with caution.
- Patients with hepatic impairment may be at increased risk of toxicity, particularly from myelosuppression; such patients should be closely monitored for development of profound myelosuppression.
- Paclitaxel is not recommended in patients who have total bilirubin >5 x ULN or AST >10 x ULN. In addition, paclitaxel is not recommended in patients with metastatic adenocarcinoma of the pancreas who have moderate to severe hepatic impairment (total bilirubin >1.5 x ULN and AST ≤10 x ULN). The starting dose should be reduced for patients with moderate or severe hepatic impairment.
### Females of Reproductive Potential and Males
- Men should be advised not to father a child while receiving paclitaxel.
- Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females.
### Immunocompromised Patients
There is no FDA guidance one the use of Paclitaxel in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Paclitaxel Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Paclitaxel and IV administrations.
# Overdosage
There is no known antidote for paclitaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.
# Pharmacology
## Mechanism of Action
Paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
## Structure
The chemical name for paclitaxel is 5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine.
Paclitaxel has the following structural formula:
Paclitaxel is a white to off-white crystalline powder with the empirical formula C47H51NO14 and a molecular weight of 853.91.
## Pharmacodynamics
There is limited information regarding Paclitaxel Pharmacodynamics in the drug label.
## Pharmacokinetics
### Absorption
- The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of paclitaxel at dose levels of 80 to 375 mg/m2 were determined in clinical studies. Paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination.
- The drug exposure (AUCs) was dose proportional over 80 to 300 mg/m2 and the pharmacokinetics of paclitaxel for paclitaxel were independent of the duration of intravenous administration.
### Distribution
- Paclitaxel is evenly distributed into blood cells and plasma and is highly bound to plasma proteins (94%). In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 µg/mL, indicated that the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel. The total volume of distribution is approximately 1741 L; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.
### Metabolism
- In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4.
### Elimination
- At the clinical dose range of 80 to 300 mg/m2, the mean total clearance of paclitaxel ranges from 13 to 30 L/h/m2, and the mean terminal half-life ranges from 13 to 27 hours.
- After a 30-minute infusion of 260 mg/m2 doses of paclitaxel, the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3’-p-hydroxypaclitaxel.
- Fecal excretion was approximately 20% of the total dose administered.
## Nonclinical Toxicology
- The carcinogenic potential of paclitaxel has not been studied.
- Paclitaxel was clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice).
- Administration of paclitaxel formulated as albumin-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a body surface area basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females.
- A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis).
- Testicular atrophy/degeneration was observed in single-dose toxicology studies in rodents administered paclitaxel formulated as albumin-bound particles at doses lower than the recommended human dose; doses were 54 mg/m2 in rodents and 175 mg/m2 in dogs.
# Clinical Studies
### Metastatic Breast Cancer
- Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of paclitaxel in metastatic breast cancer.
- In one study, paclitaxel was administered as a 30-minute infusion at a dose of 175 mg/m2 to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m2 as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.
- This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive paclitaxel at a dose of 260 mg/m2 given as a 30-minute infusion, or paclitaxel injection at 175 mg/m2 given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.
- In this trial, patients in the paclitaxel treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. There was no statistically significant difference in overall survival between the two study arms.
### Non-Small Cell Lung Cancer
- A multicenter, randomized, open-label study was conducted in 1052 chemonaive patients with Stage IIIb/IV non-small cell lung cancer to compare ABRAXANE in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m2 on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m2, following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. Treatment was administered until disease progression or development of an unacceptable toxicity. The major efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).
- In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1, and 73% were current or former smokers. Patients received a median of 6 cycles of treatment in both study arms.
- Patients in the ABRAXANE/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm (33% versus 25%). There was no statistically significant difference in overall survival between the two study arms.
### Adenocarcinoma of the Pancreas
- A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing ABRAXANE plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung disease. Patients with rapid decline in KPS (≥10%) or serum albumin (≥20%) during the 14 day screening period prior to study randomization were ineligible.
- A total of 861 patients were randomized (1:1) to the ABRAXANE/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE 125 mg/m2 as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m2 as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized to gemcitabine received 1000 mg/m2 as an intravenous infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m2 on Days 1, 8 and 15 of each subsequent 28-day cycle. Patients in both arms received treatment until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).
- In the intent to treat (all randomized) population, the median age was 63 years (range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%).
- In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects, the treatment effects on overall survival were similar to that observed in the overall study population.
# How Supplied
100 mg of paclitaxel in a single-use vial
- Individually packaged in a carton.
- NDC No.: 68817-134-50
## Storage
At 20°C to 25°C (68°F to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Paclitaxel injection may cause fetal harm. Advise patients to avoid becoming pregnant while receiving this drug. Women of childbearing potential should use effective contraceptives while receiving paclitaxel.
- Advise men not to father a child while receiving paclitaxel.
- Patients must be informed of the risk of low blood cell counts and severe and life-threatening infections and instructed to contact their physician immediately for fever or evidence of infection.
- Patients should be instructed to contact their physician for persistent vomiting, diarrhea, or signs of dehydration.
- Patients must be informed that sensory neuropathy occurs frequently with paclitaxel and patients should advise their physicians of numbness, tingling, pain or weakness involving the extremities.
- Explain to patients that alopecia, fatigue/asthenia, and myalgia/arthralgia occur frequently with paclitaxel.
- Instruct patients to contact their physician for signs of an allergic reaction, which could be severe and sometimes fatal.
- Instruct patients to contact their physician immediately for sudden onset of dry persistent cough, or shortness of breath.
# Precautions with Alcohol
Alcohol-Paclitaxel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Taxol
- Onxol
- Nov-Onxol
- Paclitaxel Novaplus
- Abraxane [2]
# Look-Alike Drug Names
There is limited information regarding Paclitaxel Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/ABI-007 | |
0f7e85c84419572d63d6d379a5ed85e96b369635 | wikidoc | ABL (gene) | ABL (gene)
Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene (previous symbol ABL) located on chromosome 9. c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene.
# Function
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9;22) translocation results in the head-to-tail fusion of the BCR and ABL1 genes, leading to a fusion gene present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for ABL1. The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.
# Clinical significance
Mutations in the ABL1 gene are associated with chronic myelogenous leukemia (CML). In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
This gene is a partner in a fusion gene with the BCR gene in the Philadelphia chromosome, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle. Second generation BCR-ABL tyrosine-kinase inhibitors are also under development
to inhibit BCR-ABL mutants resistant to imatinib.
# Interactions
Abl gene has been shown to interact with:
- ABI1,
- ABI2,
- ABL2,
- ATM,
- BCAR1,
- BCR,
- BRCA1,
- CAT,
- CBL,
- CRKL,
- DOK1,
- EPHB2,
- GPX1,
- GRB10,
- MTOR,
- GRB2,
- MDM2,
- NCK1,
- NEDD9,
- NTRK1,
- P73,
- PAG1,
- PAK2,
- PSTPIP1,
- RAD9A,
- RAD51,
- RB1,
- RFX1,
- RYBP,
- SHC1,
- SORBS2,
- SPTA1,
- SPTAN1,
- TERF1,
- VAV1, and
- YTHDC1.
# Regulation
There is some evidence that the expression of Abl is regulated by the microRNA miR-203. | ABL (gene)
Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene (previous symbol ABL) located on chromosome 9.[1] c-Abl is sometimes used to refer to the version of the gene found within the mammalian genome, while v-Abl refers to the viral gene.
# Function
The ABL1 proto-oncogene encodes a cytoplasmic and nuclear protein tyrosine kinase that has been implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene. The t(9;22) translocation results in the head-to-tail fusion of the BCR and ABL1 genes, leading to a fusion gene present in many cases of chronic myelogenous leukemia. The DNA-binding activity of the ubiquitously expressed ABL1 tyrosine kinase is regulated by CDC2-mediated phosphorylation, suggesting a cell cycle function for ABL1. The ABL1 gene is expressed as either a 6- or a 7-kb mRNA transcript, with alternatively spliced first exons spliced to the common exons 2-11.[2]
# Clinical significance
Mutations in the ABL1 gene are associated with chronic myelogenous leukemia (CML). In CML, the gene is activated by being translocated within the BCR (breakpoint cluster region) gene on chromosome 22. This new fusion gene, BCR-ABL, encodes an unregulated, cytoplasm-targeted tyrosine kinase that allows the cells to proliferate without being regulated by cytokines. This, in turn, allows the cell to become cancerous.
This gene is a partner in a fusion gene with the BCR gene in the Philadelphia chromosome, a characteristic abnormality in chronic myelogenous leukemia (CML) and rarely in some other leukemia forms. The BCR-ABL transcript encodes a tyrosine kinase, which activates mediators of the cell cycle regulation system, leading to a clonal myeloproliferative disorder. The BCR-ABL protein can be inhibited by various small molecules. One such inhibitor is imatinib mesylate, which occupies the tyrosine kinase domain and inhibits BCR-ABL's influence on the cell cycle. Second generation BCR-ABL tyrosine-kinase inhibitors are also under development
to inhibit BCR-ABL mutants resistant to imatinib.
# Interactions
Abl gene has been shown to interact with:
- ABI1,[3][4][5]
- ABI2,[6][7]
- ABL2,[6]
- ATM,[8][9][10]
- BCAR1,[11][12]
- BCR,[13][14][15]
- BRCA1,[16]
- CAT,[17]
- CBL,[18][19]
- CRKL,[20][21][22]
- DOK1,[23][24]
- EPHB2,[25]
- GPX1,[26]
- GRB10,[27][28]
- MTOR,[29]
- GRB2,[20][30]
- MDM2,[31]
- NCK1,[18][20]
- NEDD9,[32][33]
- NTRK1,[34][35]
- P73,[36][37]
- PAG1,[38]
- PAK2,[39]
- PSTPIP1,[40]
- RAD9A,[41]
- RAD51,[8]
- RB1,[42][43]
- RFX1,[44]
- RYBP,[45]
- SHC1,[13][46]
- SORBS2,[19][47]
- SPTA1,[48]
- SPTAN1,[48]
- TERF1,[10]
- VAV1,[49] and
- YTHDC1.[50]
# Regulation
There is some evidence that the expression of Abl is regulated by the microRNA miR-203.[51] | https://www.wikidoc.org/index.php/ABL_(gene) | |
f35bd102d6bfecb872e37b231a25238856589222 | wikidoc | ABO (gene) | ABO (gene)
Histo-blood group ABO system transferase is an enzyme with glycosyltransferase activity, which is encoded by the ABO gene in humans. It is ubiquitously expressed in many tissues and cell types. ABO determines the ABO blood group of an individual by modifying the oligosaccharides on cell surface glycoproteins. Variations in the sequence of the protein between individuals determine the type of modification and the blood group. The ABO gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Structure
The ABO gene resides on chromosome 9 at the band 9q34.2 and contains 7 exons. The ABO locus encodes three alleles. The A allele produces α-1,3-N-acetylgalactosamine transferase (A-transferase), which catalyzes the transfer of GalNAc residues from the UDP-GalNAc donor nucleotide to the Gal residues of the acceptor H antigen, converting the H antigen into A antigen in A and AB individuals. The B allele encodes α-1,3-galactosyl transferase (B-transferase), which catalyzes the transfer of Gal residues from the UDP-Gal donor nucleotide to the Gal residues of the acceptor H antigen, converting the H antigen into B antigen in B and AB individuals. Remarkably, the difference between the A and B glycosyltransferase enzymes is only four amino acids. The O allele lacks both enzymatic activities because of the frame shift caused by a deletion of guanine-258 in the gene which corresponds to a region near the N-terminus of the protein.This results in a frameshift and translation of an almost entirely different protein. This mutation results in a protein unable to modify oligosaccharides which end in fucose linked to galactose. Thus no A or B antigen is found in O individuals. This sugar combination is termed the H antigen. These antigens play an important role in the match of blood transfusion and organ transplantation. Other minor alleles have been found for this gene.
# Common alleles
There are six common alleles in individuals of European descent. Nearly every living human's phenotype for the ABO gene is some combination of just these six alleles:
- A
A101 (A1)
A201 (A2)
- A101 (A1)
- A201 (A2)
- B
B101 (B1)
- B101 (B1)
- O
O01 (O1)
O02 (O1v)
O03 (O2)
- O01 (O1)
- O02 (O1v)
- O03 (O2)
Many rare variants of these alleles have been found in human populations around the world.
# Clinical significance
In human cells, the ABO alleles and their encoded glycosyltransferases have been described in several oncologic conditions. Using anti-GTA/GTB monoclonal antibodies, it was demonstrated that a loss of these enzymes was correlated to malignant bladder and oral epithelia. Furthermore, the expression of ABO blood group antigens in normal human tissues is dependent the type of differentiation of the epithelium. In most human carcinomas, including oral carcinoma, a significant event as part of the underlying mechanism is decreased expression of the A and B antigens. Several studies have observed that a relative down-regulation of GTA and GTB occurs in oral carcinomas in association with tumor development. More recently, a genome wide association study (GWAS) has identified variants in the ABO locus associated with susceptibility to pancreatic cancer.
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the ABO gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). | ABO (gene)
Histo-blood group ABO system transferase is an enzyme with glycosyltransferase activity, which is encoded by the ABO gene in humans.[1][2] It is ubiquitously expressed in many tissues and cell types.[3] ABO determines the ABO blood group of an individual by modifying the oligosaccharides on cell surface glycoproteins. Variations in the sequence of the protein between individuals determine the type of modification and the blood group. The ABO gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[4]
# Structure
The ABO gene resides on chromosome 9 at the band 9q34.2 and contains 7 exons.[2] The ABO locus encodes three alleles. The A allele produces α-1,3-N-acetylgalactosamine transferase (A-transferase), which catalyzes the transfer of GalNAc residues from the UDP-GalNAc donor nucleotide to the Gal residues of the acceptor H antigen, converting the H antigen into A antigen in A and AB individuals. The B allele encodes α-1,3-galactosyl transferase (B-transferase), which catalyzes the transfer of Gal residues from the UDP-Gal donor nucleotide to the Gal residues of the acceptor H antigen, converting the H antigen into B antigen in B and AB individuals. Remarkably, the difference between the A and B glycosyltransferase enzymes is only four amino acids.[5] The O allele lacks both enzymatic activities because of the frame shift caused by a deletion of guanine-258 in the gene which corresponds to a region near the N-terminus of the protein.[6]This results in a frameshift and translation of an almost entirely different protein.[5] This mutation results in a protein unable to modify oligosaccharides which end in fucose linked to galactose. Thus no A or B antigen is found in O individuals. This sugar combination is termed the H antigen. These antigens play an important role in the match of blood transfusion and organ transplantation.[5] Other minor alleles have been found for this gene.[2]
# Common alleles
There are six common alleles in individuals of European descent. Nearly every living human's phenotype for the ABO gene is some combination of just these six alleles:[7][8]
- A
A101 (A1)
A201 (A2)
- A101 (A1)
- A201 (A2)
- B
B101 (B1)
- B101 (B1)
- O
O01 (O1)
O02 (O1v)
O03 (O2)
- O01 (O1)
- O02 (O1v)
- O03 (O2)
Many rare variants of these alleles have been found in human populations around the world.
# Clinical significance
In human cells, the ABO alleles and their encoded glycosyltransferases have been described in several oncologic conditions.[9] Using anti-GTA/GTB monoclonal antibodies, it was demonstrated that a loss of these enzymes was correlated to malignant bladder and oral epithelia.[10][11] Furthermore, the expression of ABO blood group antigens in normal human tissues is dependent the type of differentiation of the epithelium. In most human carcinomas, including oral carcinoma, a significant event as part of the underlying mechanism is decreased expression of the A and B antigens.[12] Several studies have observed that a relative down-regulation of GTA and GTB occurs in oral carcinomas in association with tumor development.[12][13] More recently, a genome wide association study (GWAS) has identified variants in the ABO locus associated with susceptibility to pancreatic cancer.[14][15]
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the ABO gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[4] | https://www.wikidoc.org/index.php/ABO_(gene) | |
26609609bf8a9386cc59e84ce0295ccbf70e2bf7 | wikidoc | ACD (gene) | ACD (gene)
Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ACD gene.
# Function
This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.
TPP1 is a component of the telomere-specific shelterin complex, which facilitats the replication of the double-stranded telomeric DNA tracts and protects the telomeric end from unregulated DNA repair activities. TPP1 mainly functions as a regulator of telomerase recruitment, activation, and regulation. Although TPP1 was originally described as a bridging factor between TRF1 and TRF2, which participate in a pathway with POT1 as a negative regulator of telomerase-dependent telomere length control, more recent studies suggest that TPP1 could directly promotes telomerase activity at the telomere. A part of the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold named TEL patch that interacts with the catalytic subunit of telomerase, hTERT, has been proven essential for telomerase activation. What’s more, TPP1 has been demonstrated the only pathway required for recruitment of telomerase to chromosome ends, and it also defines telomere length homeostasis in hESCs.
# Interactions
ACD (gene) has been shown to interact with POT1 and TINF2.
- POT1
- hTERT
- TIN2
- TRF1
- TRF2
- Telomerase | ACD (gene)
Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ACD gene.[1][2][3]
# Function
This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I.[3]
TPP1 is a component of the telomere-specific shelterin complex, which facilitats the replication of the double-stranded telomeric DNA tracts and protects the telomeric end from unregulated DNA repair activities. TPP1 mainly functions as a regulator of telomerase recruitment, activation, and regulation.[4] Although TPP1 was originally described as a bridging factor between TRF1 and TRF2, which participate in a pathway with POT1 as a negative regulator of telomerase-dependent telomere length control, [5] more recent studies suggest that TPP1 could directly promotes telomerase activity at the telomere.[6] A part of the TPP1 oligonucleotide/oligosaccharide-binding (OB) fold named TEL patch that interacts with the catalytic subunit of telomerase, hTERT, has been proven essential for telomerase activation.[7] What’s more, TPP1 has been demonstrated the only pathway required for recruitment of telomerase to chromosome ends, and it also defines telomere length homeostasis in hESCs.[7]
# Interactions
ACD (gene) has been shown to interact with POT1[1][2][8] and TINF2.[1][2]
- POT1 [9]
- hTERT [10] [11]
- TIN2 [12]
- TRF1 [12]
- TRF2 [12]
- Telomerase [13] | https://www.wikidoc.org/index.php/ACD_(gene) | |
47dedce2cbe76f08ebd9ff7095c57053a91b3196 | wikidoc | Beta-actin | Beta-actin
Beta-actin (human gene and protein symbol ACTB/ACTB) is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins that are involved in cell motility, structure and integrity. Alpha actins are a major constituent of the contractile apparatus.
# Interactions
Beta-actin has been shown to interact with SPTBN2. In addition, RNA-binding protein Sam68 was found to interact with the mRNA encoding β-actin, which regulates the synaptic formation of the dendritic spines with its cytoskeletal components.
Beta-actin has been shown to activate eNOS, thereby increasing NO production. An eight-amino acid residue (326-333) in actin has been shown to mediate the interaction between actin and eNOS
# Clinical relevance
Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma.
# Applications
Beta actin is usually used as a loading control, for among others, the integrity of cells, protein degradation, in PCR and Western blotting. Its molecular weight is approximately 42 kDa. | Beta-actin
Beta-actin (human gene and protein symbol ACTB/ACTB) is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins[1][2] that are involved in cell motility, structure and integrity. Alpha actins are a major constituent of the contractile apparatus.[3]
# Interactions
Beta-actin has been shown to interact with SPTBN2.[4][5] In addition, RNA-binding protein Sam68 was found to interact with the mRNA encoding β-actin, which regulates the synaptic formation of the dendritic spines with its cytoskeletal components.
Beta-actin has been shown to activate eNOS, thereby increasing NO production. An eight-amino acid residue (326-333) in actin has been shown to mediate the interaction between actin and eNOS[6]
# Clinical relevance
Recurrent mutations in this gene have been associated to cases of diffuse large B-cell lymphoma.[7]
# Applications
Beta actin is usually used as a loading control, for among others, the integrity of cells, protein degradation, in PCR and Western blotting. Its molecular weight is approximately 42 kDa. | https://www.wikidoc.org/index.php/ACTB | |
c14b515f0e491bf68335a16d1bbc7918829400e7 | wikidoc | AGK (gene) | AGK (gene)
The human gene AGK encodes the enzyme mitochondrial acylglycerol kinase.
The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. It catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10.
Diseases associated with AGK include cataracts and cardiomyopathy. An important paralog of this gene is CERKL.
# Structure
The AGK gene is located on the 7th chromosome, with its specific location being 7q34. The gene contains 18 exons. AGK encodes a 47.1 kDa protein that is composed of 422 amino acids; 32 peptides have been observed through mass spectrometry data.
# Function
Acylglycerol kinase synthesizes phosphatidic and lysophosphatidic acids. The enzyme uses ATP to put a phosphate group on acyl glycerol and diacylglycerol. It catalyzes the following reactions:
ATP + acylglycerol = ADP + acyl-sn-glycerol 3-phosphate.
ATP + 1,2-diacyl-sn-glycerol = ADP + 1,2-diacyl-sn-glycerol 3-phosphate.
The enzyme is involved in the more general pathway of fatty acid metabolism. AGK also has an implicated role in the assembly of the adenine nucleotide translocator in the inner mitochondrial membrane.
# Clinical significance
Mutations in the AGK gene were the first to be implicated in isolated cataract development, although it is unclear whether these mutations cause a change in lipid composition of the lenses, or if signaling results in the defect. This gene has also been associated with Sengers syndrome. Two different phenotypes have been observed. One form of the disorder presented as vascular strokes, lactic acidosis, cardiomyopathy and cataracts, abnormal muscle cell histopathology and mitochondrial function. In those patients, there was also a markedly high rate of citrate synthase. The second phenotype presented with similar clinical symptoms, but no strokes. As phosphatidic acid is also involved in the synthesis of phospholipids, its loss will result in changes to the lipid composition of the inner mitochondrial membrane. These effects manifest as cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue.
AGK expression has also been correlated with certain cancer phenotypes. AGK expression, in coordination with AGX, was not detected in non-neoplastic epithelia, while both were weakly expressed in the majority of high-grade intra-epithelial neoplasia (HG-PIN). Expressions of both enzymes were significantly correlated with primary Gleason grade of cancer foci and capsular invasion. Overexpression of AGK sustains constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly increases STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. In prostate cancer, AGK expression amplifies EGF signaling pathways, thus playing a significant role in the development of prostate cancer. It’s also correlated tumor-nodule-metastasis (TNM) classification breast cancer, and an overall shorter overall survival.
# Interactions
In the progression of diabetic retinopathy, the ATX-AGK-LPA signaling axis plays a significant role.
In the proliferation of prostate cancer, AGK interacts with and regulates PC-3 prostate cancer cells markedly increased formation and secretion of LPA. This increase also affects the EGF receptor and sustained activation of extracellular signal related kinase (ERK) 1/2, culminating in enhanced cell proliferation. Acylglycerol kinase also augments JAK2/STAT3 signaling in esophageal squamous cells. | AGK (gene)
The human gene AGK encodes the enzyme mitochondrial acylglycerol kinase.[1][2][3][4]
The protein encoded by this gene is a mitochondrial membrane protein involved in lipid and glycerolipid metabolism. It catalyzes the formation of phosphatidic and lysophosphatidic acids. Defects in this gene have been associated with mitochondrial DNA depletion syndrome 10.
Diseases associated with AGK include cataracts and cardiomyopathy. An important paralog of this gene is CERKL.
# Structure
The AGK gene is located on the 7th chromosome, with its specific location being 7q34. The gene contains 18 exons.[4] AGK encodes a 47.1 kDa protein that is composed of 422 amino acids; 32 peptides have been observed through mass spectrometry data.[5][6]
# Function
Acylglycerol kinase synthesizes phosphatidic and lysophosphatidic acids. The enzyme uses ATP to put a phosphate group on acyl glycerol and diacylglycerol. It catalyzes the following reactions:
ATP + acylglycerol = ADP + acyl-sn-glycerol 3-phosphate.
ATP + 1,2-diacyl-sn-glycerol = ADP + 1,2-diacyl-sn-glycerol 3-phosphate.
The enzyme is involved in the more general pathway of fatty acid metabolism. AGK also has an implicated role in the assembly of the adenine nucleotide translocator in the inner mitochondrial membrane.
[7]
# Clinical significance
Mutations in the AGK gene were the first to be implicated in isolated cataract development, although it is unclear whether these mutations cause a change in lipid composition of the lenses, or if signaling results in the defect.[8] This gene has also been associated with Sengers syndrome. Two different phenotypes have been observed. One form of the disorder presented as vascular strokes, lactic acidosis, cardiomyopathy and cataracts, abnormal muscle cell histopathology and mitochondrial function. In those patients, there was also a markedly high rate of citrate synthase. The second phenotype presented with similar clinical symptoms, but no strokes. As phosphatidic acid is also involved in the synthesis of phospholipids, its loss will result in changes to the lipid composition of the inner mitochondrial membrane. These effects manifest as cataract formation in the eye, respiratory chain dysfunction and cardiac hypertrophy in heart tissue.[9]
AGK expression has also been correlated with certain cancer phenotypes. AGK expression, in coordination with AGX, was not detected in non-neoplastic epithelia, while both were weakly expressed in the majority of high-grade intra-epithelial neoplasia (HG-PIN). Expressions of both enzymes were significantly correlated with primary Gleason grade of cancer foci and capsular invasion.[10] Overexpression of AGK sustains constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly increases STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer.[11] In prostate cancer, AGK expression amplifies EGF signaling pathways, thus playing a significant role in the development of prostate cancer.[12] It’s also correlated tumor-nodule-metastasis (TNM) classification breast cancer, and an overall shorter overall survival.[13]
# Interactions
In the progression of diabetic retinopathy, the ATX-AGK-LPA signaling axis plays a significant role.[14]
In the proliferation of prostate cancer, AGK interacts with and regulates PC-3 prostate cancer cells markedly increased formation and secretion of LPA. This increase also affects the EGF receptor and sustained activation of extracellular signal related kinase (ERK) 1/2, culminating in enhanced cell proliferation.[12] Acylglycerol kinase also augments JAK2/STAT3 signaling in esophageal squamous cells.[11] | https://www.wikidoc.org/index.php/AGK_(gene) | |
24ee267fdc374dad3c8bdd94eaf81a94dd251835 | wikidoc | Felodipine | Felodipine
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# Overview
Felodipine is a calcium channel blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include peripheral edema，flushing，indigestion，headache，upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Felodipine
- Dosing information
- Recommended starting dosage: 5 mg PO qd.
- These adjustments should occur generally at intervals of not less than 2 weeks.
- The recommended dosage range is 2.5-10 mg PO qd, depending on the patient's response.
- Modification of the recommended dosage is usually not required in patients with renal impairment.
- Felodipine extended-release tablets should regularly be taken either without food or with a light meal. Felodipine extended-release tablets should be swallowed whole and not crushed or chewed.
- Geriatric Use - Patients over 65 years of age are likely to develop higher plasma concentrations of felodipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (2.5 mg daily). Elderly patients should have their blood pressure closely monitored during any dosage adjustment.
- Patients with Impaired Liver Function - Patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine extended-release tablets; therefore, patients should have their blood pressure monitored closely during dosage adjustment of felodipine extended-release tablets.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of felodipine sandbox in adult patients.
### Non–Guideline-Supported Use
### Angina
- Dosing information
- Initial dosage: 5 mg/day
- Following 10 weeks: 10 mg/day ， ，
- 2.5-5 mg PO bid or 10-20 mg PO qd
- 10 mg PO qd
- 20 mg PO qd
### Arteriosclerotic Vascular Disease
- Dosing information
- Not applicable
### Chronic Cyclosporin A Nephrotoxicity
- Dosing information
- 10 mg/day ,
- 4 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of felodipine sandbox in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of felodipine sandbox in pediatric patients.
# Contraindications
- Felodipine extended-release tablets are contraindicated in patients who are hypersensitive to this product.
# Warnings
Hypotension – Felodipine, like other calcium antagonists, may occasionally precipitate significant hypotension and, rarely, syncope. It may lead to reflex tachycardia which in susceptible individuals may precipitate angina pectoris.
Heart Failure – Although acute hemodynamic studies in a small number of patients with NYHA Class II or III heart failure treated with felodipine have not demonstrated negative inotropic effects, safety in patients with heart failure has not been established. Caution, therefore, should be exercised when using felodipine in patients with heart failure or compromised ventricular function, particularly in combination with a beta blocker.
Patients with Impaired Liver Function – Patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine; therefore, a starting dose of 2.5 mg once a day is recommended. These patients should have their blood pressure monitored closely during dosage adjustment of felodipine.
Peripheral Edema – Peripheral edema, generally mild and not associated with generalized fluid retention, was the most common adverse event in the clinical trials. The incidence of peripheral edema was both dose and age dependent. Frequency of peripheral edema ranged from about 10% in patients under 50 years of age taking 5 mg daily to about 30% in those over 60 years of age taking 20 mg daily. This adverse effect generally occurs within 2−3 weeks of the initiation of treatment.
# Adverse Reactions
## Clinical Trials Experience
- In controlled studies in the United States and overseas, approximately 3000 patients were treated with felodipine as either the extended-release or the immediate-release formulation.
- The most common clinical adverse events reported with felodipine extended-release administered as monotherapy at the recommended dosage range of 2.5 mg to 10 mg once a day were peripheral edema and headache. Peripheral edema was generally mild, but it was age and dose related and resulted in discontinuation of therapy in about 3% of the enrolled patients. Discontinuation of therapy due to any clinical adverse event occurred in about 6% of the patients receiving felodipine extended-release tablets, principally for peripheral edema, headache, or flushing.
- Adverse events that occurred with an incidence of 1.5% or greater at any of the recommended doses of 2.5 mg to 10 mg once a day (felodipine extended-release tablets, N = 861; Placebo, N = 334), without regard to causality, are compared to placebo and are listed by dose in the table below. These events are reported from controlled clinical trials with patients who were randomized to a fixed dose of felodipine extended-release tablets or titrated from an initial dose of 2.5 mg or 5 mg once a day. A dose of 20 mg once a day has been evaluated in some clinical studies. Although the antihypertensive effect of felodipine extended-release tablets is increased at 20 mg once a day, there is a disproportionate increase in adverse events, especially those associated with vasodilatory effects.
- Adverse events that occurred in 0.5% up to 1.5% of patients who received felodipine extended-release tablets in all controlled clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day, and serious adverse events that occurred at a lower rate, or events reported during marketing experience (those lower rate events are in italics) are listed below. These events are listed in order of decreasing severity within each category, and the relationship of these events to administration of felodipine extended-release tablets are uncertain:
Body as a Whole: Chest pain, facial edema, flu-like illness
Cardiovascular: Myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia, tachycardia, premature beats;
Digestive: Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation
Endocrine: Gynecomastia
Hematologic: Anemia
Metabolic: ALT (SGPT) increased
Musculoskeletal: Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain
Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido
Respiratory: Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection
Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis
Special Senses: Visual disturbances
Urogenital: Impotence, urinary frequency, urinary urgency, dysuria, polyuria.
Gingival Hyperplasia: Gingival hyperplasia, usually mild, occurred in < 0.5% of patients in controlled studies. This condition may be avoided or may regress with improved dental hygiene.
### Clinical Laboratory Test Findings
Serum Electrolytes - No significant effects on serum electrolytes were observed during short- and long-term therapy.
Serum Glucose - No significant effects on fasting serum glucose were observed in patients treated with felodipine extended-release tablets in the U.S. controlled study.
Liver Enzymes - 1 of 2 episodes of elevated serum transaminases decreased once drug was discontinued in clinical studies; no follow-up was available for the other patient.
## Postmarketing Experience
FDA package insert for felodipine contains no information regarding Post marketing adverse reactions.
# Drug Interactions
CYP3A4 Inhibitors – Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or due to a decrease in metabolism. These increases in concentration may lead to increased effects, (lower blood pressure and increased heart rate). These effects have been observed with co-administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be taken. The following specific interactions have been reported:
Itraconazole – Co-administration of another extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of felodipine.
Erythromycin – Co-administration of felodipine with erythromycin resulted in approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of felodipine.
Grapefruit juice – Co-administration of felodipine with grapefruit juice resulted in more than 2-fold increase in the AUC and Cmax, but no prolongation in the half-life of felodipine.
Cimetidine – Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the Cmax, of felodipine.
Beta-Blocking Agents – A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and Cmax of metoprolol, however, were increased approximately 31 and 38%, respectively. In controlled clinical trials, however, beta blockers including metoprolol were concurrently administered with felodipine and were well tolerated.
Digoxin – When given concomitantly with felodipine the pharmacokinetics of digoxin in patients with heart failure were not significantly altered.
Anticonvulsants – In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, phenytoin, carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients.
Tacrolimus – Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, the tacrolimus blood concentration should be followed and the tacrolimus dose may need to be adjusted.
Other Concomitant Therapy – In healthy subjects there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone.
Interaction with Food
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
### Teratogenic Effects
- Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day (from 0.8 to 8 times1 the maximum recommended human dose on a mg/m2 basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not observed in rats given felodipine.
- In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.
### Non Teratogenic Effects
- A prolongation of parturition with difficult labor and an increased frequency of fetal and early postnatal deaths were observed in rats administered doses of 9.6 mg/kg/day (8 times1 the maximum human dose on a mg/m2 basis) and above.
- Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m2 basis). This effect occurred only in pregnant rabbits and regressed during lactation.
Similar changes in the mammary glands were not observed in rats or monkeys.
- There are no adequate and well-controlled studies in pregnant women. If felodipine extended-release tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery and on the mammary glands of pregnant females.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Felodipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Felodipine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is secreted in human milk and because of the potential for serious adverse reactions from felodipine in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of felodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Pharmacokinetics, however, indicate that the availability of felodipine is increased in older patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Felodipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Felodipine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Felodipine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Felodipine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Felodipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Felodipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
FDA package insert for felodipine contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV compatibility.
# Overdosage
- Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and 2250 mg/kg in male and female rats, respectively, caused significant lethality.
- In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on admission to hospital; he subsequently recovered without significant sequelae.
- Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia.
- If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The administration of intravenous fluids may be useful to treat hypotensiondue to overdosage with calcium antagonists. In case of accompanying bradycardia, atropine (0.5−1 mg) should be administered intravenously. Sympathomimetic drugs may also be given if the physician feels they are warranted.
- It has not been established whether felodipine can be removed from the circulation by hemodialysis.
- To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.
# Pharmacology
## Mechanism of Action
- Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers). It reversibly competes with an itrendipine and/or other calcium channel blockers for dihydropyridine binding sites, blocks voltage-dependent Ca++ currents in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.
- In vitro studies show that the effects of felodipine on contractile processes are selective, with greater effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals.
- The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular Effects). With the exception of a mild diuretic effect seen in several animal species and man, the effects of felodipine are accounted for by its effects on peripheral vascular resistance.
## Structure
- Felodipine (felodipine) is a calcium antagonist (calcium channel blocker). Felodipine is a dihydropyridine derivative that is chemically described as ± ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. Its empirical formula is C18H19Cl2NO4 and its structural formula is:
- Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture.
- Tablets felodipine provide extended release of felodipine. They are available as tablets containing 2.5 mg, 5 mg, or 10 mg of felodipine for oral administration. In addition to the active ingredient felodipine, the tablets contain the following inactive ingredients: Tablets felodipine 2.5 mg — hydroxypropyl cellulose, lactose, FD&C Blue 2, sodium stearyl fumarate, titanium dioxide, yellow iron oxide, and other ingredients. Tablets Felodipine 5 mg and 10 mg — cellulose, red and yellow oxide, lactose, polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and other ingredients.
## Pharmacodynamics
- Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-pass metabolism. The systemic bioavailability of felodipine is approximately 20%. Mean peak concentrations following the administration of felodipine are reached in 2.5 to 5 hours. Both peak plasma concentration and the area under the plasma concentration time curve (AUC) increase linearly with doses up to 20 mg. Felodipine is greater than 99% bound to plasma proteins.
- Following intravenous administration, the plasma concentration of felodipine declined triexponentially with mean disposition half-lives of 4.8 minutes, 1.5 hours, and 9.1 hours. The mean contributions of the three individual phases to the overall AUC were 15, 40, and 45%, respectively, in the order of increasing t1/2.
- Following oral administration of the immediate-release formulation, the plasma level of felodipine also declined polyexponentially with a mean terminal t1/2 of 11 to 16 hours. The mean peak and trough steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given once a day to normal volunteers, were 20 and 0.5 nmol/L, respectively. The trough plasma concentration of felodipine in most individuals was substantially below the concentration needed to effect a half-maximal decline in blood pressure (EC50) , thus precluding once-a-day dosing with the immediate-release formulation.
- Following administration of a 10-mg dose of felodipine, the extended-release formulation, to young, healthy volunteers, mean peak and trough steady-state plasma concentrations of felodipine were 7 and 2 nmol/L, respectively. Corresponding values in hypertensive patients (mean age 64) after a 20-mg dose of felodipine were 23 and 7 nmol/L. Since the EC50 for felodipine is 4 to 6 nmol/L, a 5- to 10-mg dose of felodipine in some patients, and a 20-mg dose in others, would be expected to provide an antihypertensive effect that persists for 24 hours.
- The systemic plasma clearance of felodipine in young healthy subjects is about 0.8 L/min, and the apparent volume of distribution is about 10 L/kg.
- Following an oral or intravenous dose of 14C-labeled felodipine in man, about 70% of the dose of radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact felodipine is recovered in the urine and feces (< 0.5%). Six metabolites, which account for 23% of the oral dose, have been identified; none has significant vasodilating activity.
- Following administration of felodipine to hypertensive patients, mean peak plasma concentrations at steady state are about 20% higher than after a single dose. Blood pressure response is correlated with plasma concentrations of felodipine.
- The bioavailability of felodipine is influenced by the presence of food. When administered either with a high fat or carbohydrate diet, Cmax is increased by approximately 60%; AUC is unchanged. When felodipine was administered after a light meal (orange juice, toast, and cereal), however, there is no effect on felodipine’s pharmacokinetics. The bioavailability of felodipine was increased approximately two-fold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of Felodipine. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine.
Geriatric Use – Plasma concentrations of felodipine, after a single dose and at steady state, increase with age. Mean clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that of young volunteers (mean age 26). At steady state mean AUC for young patients was 39% of that for the elderly. Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young and the elderly.
Hepatic Dysfunction – In patients with hepatic disease, the clearance of felodipine was reduced to about 60% of that seen in normal young volunteers.
- Renal impairment does not alter the plasma concentration profile of felodipine; although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive.
- Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.
## Pharmacokinetics
## Cardiovascular Effects
- Following administration of felodipine, a reduction in blood pressure generally occurs within 2 to 5 hours. During chronic administration, substantial blood pressure control lasts for 24 hours, with trough reductions in diastolic blood pressure approximately 40−50% of peak reductions. The antihypertensive effect is dose dependent and correlates with the plasma concentration of felodipine.
- A reflex increase in heart rate frequently occurs during the first week of therapy; this increase attenuates over time. Heart rate increases of 5−10 beats per minute may be seen during chronic dosing. The increase is inhibited by beta-blocking agents.
- The P-R interval of the ECG is not affected by felodipine when administered alone or in combination with a beta-blocking agent. Felodipine alone or in combination with a beta-blocking agent has been shown, in clinical and electrophysiologic studies, to have no significant effect on cardiac conduction (P-R, P-Q, and H-V intervals).
- In clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in this population.
## Renal/Endocrine Effects
- Renal vascular resistance is decreased by felodipine while glomerular filtration rate remains unchanged. Mild diuresis, natriuresis, and kaliuresis have been observed during the first week of therapy. No significant effects on serum electrolytes were observed during short- and long-term therapy.
- In clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been observed.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61 times1 the maximum recommended human dose on a mg/m2 basis), a dose-related increase in the incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61 times1 the maximum recommended human dose on a mg/m2 basis). Felodipine, at the doses employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly secondary to these hormonal effects which have not been observed in man.
- In this same rat study a dose-related increase in the incidence of focal squamous cell hyperplasia compared to control was observed in the esophageal groove of male and female rats in all dose groups. No other drug-related esophageal or gastric pathology was observed in the rats or with chronic administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to the esophageal groove.
- Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day (61 times1 the maximum recommended human dose on a mg/m2 basis) for periods of up to 80 weeks in males and 99 weeks in females.
- Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times1 the maximum recommended human dose on a mg/m2 basis) or in vitro in a human lymphocyte chromosome aberration assay.
- A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 mg/kg/day (up to 24 times1 the maximum recommended human dose on a mg/m2basis) showed no significant effect of felodipine on reproductive performance.
# Clinical Studies
- Felodipine produces dose-related decreases in systolic and diastolic blood pressure as demonstrated in six placebo-controlled, dose response studies using either immediate-release or extended-release dosage forms. These studies enrolled over 800 patients on active treatment, at total daily doses ranging from 2.5 to 20 mg. In those studies felodipine was administered either as monotherapy or was added to beta blockers. The results of the 2 studies with felodipine given once daily as monotherapy are shown in the table below:
# How Supplied
- Felodipine Extended-Release Tablets, USP are available containing 2.5 mg, 5 mg or 10 mg of felodipine, USP.
- The 2.5 mg tablet is a yellow colored, circular shaped, biconvex, film coated tablet de-bossed with 'I31' on one side and plain on other side.
- They are available as follows:
- The 5 mg tablet is a light yellow colored, circular shaped, biconvex, film coated tablet de-bossed with 'I32' on one side and plain on other side.
- They are available as follows:
- The 10 mg tablet is a white colored, circular shaped, biconvex, film coated tablet de-bossed with 'I33' on one side and plain on other side.
- They are available as follows:
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
- Manufactured for:
- Heritage Pharmaceuticals Inc.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to take felodipine extended-release tablets whole and not to crush or chew the tablets. They should be told that mild gingival hyperplasia (gum swelling) has been reported. Good dental hygiene decreases its incidence and severity.
NOTE: As with many other drugs, certain advice to patients being treated with felodipine extended-release tablets are warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
# Precautions with Alcohol
Alcohol-Felodipine sandbox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Plendil
# Look-Alike Drug Names
Felodipine - Isordil
# Drug Shortage Status
# Price | Felodipine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2], Rabin Bista, M.B.B.S. [3]
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# Overview
Felodipine is a calcium channel blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include peripheral edema，flushing，indigestion，headache，upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Felodipine
- Dosing information
- Recommended starting dosage: 5 mg PO qd.
- These adjustments should occur generally at intervals of not less than 2 weeks.
- The recommended dosage range is 2.5-10 mg PO qd, depending on the patient's response.
- Modification of the recommended dosage is usually not required in patients with renal impairment.
- Felodipine extended-release tablets should regularly be taken either without food or with a light meal. Felodipine extended-release tablets should be swallowed whole and not crushed or chewed.
- Geriatric Use - Patients over 65 years of age are likely to develop higher plasma concentrations of felodipine. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range (2.5 mg daily). Elderly patients should have their blood pressure closely monitored during any dosage adjustment.
- Patients with Impaired Liver Function - Patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine extended-release tablets; therefore, patients should have their blood pressure monitored closely during dosage adjustment of felodipine extended-release tablets.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of felodipine sandbox in adult patients.
### Non–Guideline-Supported Use
### Angina
- Dosing information
- Initial dosage: 5 mg/day
- Following 10 weeks: 10 mg/day [1]， [2]， [3]
- 2.5-5 mg PO bid or 10-20 mg PO qd [3]
- 10 mg PO qd [4]
- 20 mg PO qd [5]
### Arteriosclerotic Vascular Disease
- Dosing information
- Not applicable
### Chronic Cyclosporin A Nephrotoxicity
- Dosing information
- 10 mg/day [6], [7]
- 4 mg/day [8]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of felodipine sandbox in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of felodipine sandbox in pediatric patients.
# Contraindications
- Felodipine extended-release tablets are contraindicated in patients who are hypersensitive to this product.
# Warnings
Hypotension – Felodipine, like other calcium antagonists, may occasionally precipitate significant hypotension and, rarely, syncope. It may lead to reflex tachycardia which in susceptible individuals may precipitate angina pectoris.
Heart Failure – Although acute hemodynamic studies in a small number of patients with NYHA Class II or III heart failure treated with felodipine have not demonstrated negative inotropic effects, safety in patients with heart failure has not been established. Caution, therefore, should be exercised when using felodipine in patients with heart failure or compromised ventricular function, particularly in combination with a beta blocker.
Patients with Impaired Liver Function – Patients with impaired liver function may have elevated plasma concentrations of felodipine and may respond to lower doses of felodipine; therefore, a starting dose of 2.5 mg once a day is recommended. These patients should have their blood pressure monitored closely during dosage adjustment of felodipine.
Peripheral Edema – Peripheral edema, generally mild and not associated with generalized fluid retention, was the most common adverse event in the clinical trials. The incidence of peripheral edema was both dose and age dependent. Frequency of peripheral edema ranged from about 10% in patients under 50 years of age taking 5 mg daily to about 30% in those over 60 years of age taking 20 mg daily. This adverse effect generally occurs within 2−3 weeks of the initiation of treatment.
# Adverse Reactions
## Clinical Trials Experience
- In controlled studies in the United States and overseas, approximately 3000 patients were treated with felodipine as either the extended-release or the immediate-release formulation.
- The most common clinical adverse events reported with felodipine extended-release administered as monotherapy at the recommended dosage range of 2.5 mg to 10 mg once a day were peripheral edema and headache. Peripheral edema was generally mild, but it was age and dose related and resulted in discontinuation of therapy in about 3% of the enrolled patients. Discontinuation of therapy due to any clinical adverse event occurred in about 6% of the patients receiving felodipine extended-release tablets, principally for peripheral edema, headache, or flushing.
- Adverse events that occurred with an incidence of 1.5% or greater at any of the recommended doses of 2.5 mg to 10 mg once a day (felodipine extended-release tablets, N = 861; Placebo, N = 334), without regard to causality, are compared to placebo and are listed by dose in the table below. These events are reported from controlled clinical trials with patients who were randomized to a fixed dose of felodipine extended-release tablets or titrated from an initial dose of 2.5 mg or 5 mg once a day. A dose of 20 mg once a day has been evaluated in some clinical studies. Although the antihypertensive effect of felodipine extended-release tablets is increased at 20 mg once a day, there is a disproportionate increase in adverse events, especially those associated with vasodilatory effects.
- Adverse events that occurred in 0.5% up to 1.5% of patients who received felodipine extended-release tablets in all controlled clinical trials at the recommended dosage range of 2.5 mg to 10 mg once a day, and serious adverse events that occurred at a lower rate, or events reported during marketing experience (those lower rate events are in italics) are listed below. These events are listed in order of decreasing severity within each category, and the relationship of these events to administration of felodipine extended-release tablets are uncertain:
Body as a Whole: Chest pain, facial edema, flu-like illness
Cardiovascular: Myocardial infarction, hypotension, syncope, angina pectoris, arrhythmia, tachycardia, premature beats;
Digestive: Abdominal pain, diarrhea, vomiting, dry mouth, flatulence, acid regurgitation
Endocrine: Gynecomastia
Hematologic: Anemia
Metabolic: ALT (SGPT) increased
Musculoskeletal: Arthralgia, back pain, leg pain, foot pain, muscle cramps, myalgia, arm pain, knee pain, hip pain
Nervous/Psychiatric: Insomnia, depression, anxiety disorders, irritability, nervousness, somnolence, decreased libido
Respiratory: Dyspnea, pharyngitis, bronchitis, influenza, sinusitis, epistaxis, respiratory infection
Skin: Angioedema, contusion, erythema, urticaria, leukocytoclastic vasculitis
Special Senses: Visual disturbances
Urogenital: Impotence, urinary frequency, urinary urgency, dysuria, polyuria.
Gingival Hyperplasia: Gingival hyperplasia, usually mild, occurred in < 0.5% of patients in controlled studies. This condition may be avoided or may regress with improved dental hygiene.
### Clinical Laboratory Test Findings
Serum Electrolytes - No significant effects on serum electrolytes were observed during short- and long-term therapy.
Serum Glucose - No significant effects on fasting serum glucose were observed in patients treated with felodipine extended-release tablets in the U.S. controlled study.
Liver Enzymes - 1 of 2 episodes of elevated serum transaminases decreased once drug was discontinued in clinical studies; no follow-up was available for the other patient.
## Postmarketing Experience
FDA package insert for felodipine contains no information regarding Post marketing adverse reactions.
# Drug Interactions
CYP3A4 Inhibitors – Felodipine is metabolized by CYP3A4. Co-administration of CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice, cimetidine) with felodipine may lead to several-fold increases in the plasma levels of felodipine, either due to an increase in bioavailability or due to a decrease in metabolism. These increases in concentration may lead to increased effects, (lower blood pressure and increased heart rate). These effects have been observed with co-administration of itraconazole (a potent CYP3A4 inhibitor). Caution should be used when CYP3A4 inhibitors are co-administered with felodipine. A conservative approach to dosing felodipine should be taken. The following specific interactions have been reported:
Itraconazole – Co-administration of another extended release formulation of felodipine with itraconazole resulted in approximately 8-fold increase in the AUC, more than 6-fold increase in the Cmax, and 2-fold prolongation in the half-life of felodipine.
Erythromycin – Co-administration of felodipine with erythromycin resulted in approximately 2.5-fold increase in the AUC and Cmax, and about 2-fold prolongation in the half-life of felodipine.
Grapefruit juice – Co-administration of felodipine with grapefruit juice resulted in more than 2-fold increase in the AUC and Cmax, but no prolongation in the half-life of felodipine.
Cimetidine – Co-administration of felodipine with cimetidine (a non-specific CYP-450 inhibitor) resulted in an increase of approximately 50% in the AUC and the Cmax, of felodipine.
Beta-Blocking Agents – A pharmacokinetic study of felodipine in conjunction with metoprolol demonstrated no significant effects on the pharmacokinetics of felodipine. The AUC and Cmax of metoprolol, however, were increased approximately 31 and 38%, respectively. In controlled clinical trials, however, beta blockers including metoprolol were concurrently administered with felodipine and were well tolerated.
Digoxin – When given concomitantly with felodipine the pharmacokinetics of digoxin in patients with heart failure were not significantly altered.
Anticonvulsants – In a pharmacokinetic study, maximum plasma concentrations of felodipine were considerably lower in epileptic patients on long-term anticonvulsant therapy (eg, phenytoin, carbamazepine, or phenobarbital) than in healthy volunteers. In such patients, the mean area under the felodipine plasma concentration-time curve was also reduced to approximately 6% of that observed in healthy volunteers. Since a clinically significant interaction may be anticipated, alternative antihypertensive therapy should be considered in these patients.
Tacrolimus – Felodipine may increase the blood concentration of tacrolimus. When given concomitantly with felodipine, the tacrolimus blood concentration should be followed and the tacrolimus dose may need to be adjusted.
Other Concomitant Therapy – In healthy subjects there were no clinically significant interactions when felodipine was given concomitantly with indomethacin or spironolactone.
Interaction with Food
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
### Teratogenic Effects
- Studies in pregnant rabbits administered doses of 0.46, 1.2, 2.3 and 4.6 mg/kg/day (from 0.8 to 8 times1 the maximum recommended human dose on a mg/m2 basis) showed digital anomalies consisting of reduction in size and degree of ossification of the terminal phalanges in the fetuses. The frequency and severity of the changes appeared dose related and were noted even at the lowest dose. These changes have been shown to occur with other members of the dihydropyridine class and are possibly a result of compromised uterine blood flow. Similar fetal anomalies were not observed in rats given felodipine.
- In a teratology study in cynomolgus monkeys, no reduction in the size of the terminal phalanges was observed, but an abnormal position of the distal phalanges was noted in about 40% of the fetuses.
### Non Teratogenic Effects
- A prolongation of parturition with difficult labor and an increased frequency of fetal and early postnatal deaths were observed in rats administered doses of 9.6 mg/kg/day (8 times1 the maximum human dose on a mg/m2 basis) and above.
- Significant enlargement of the mammary glands, in excess of the normal enlargement for pregnant rabbits, was found with doses greater than or equal to 1.2 mg/kg/day (2.1 times the maximum human dose on a mg/m2 basis). This effect occurred only in pregnant rabbits and regressed during lactation.
Similar changes in the mammary glands were not observed in rats or monkeys.
- There are no adequate and well-controlled studies in pregnant women. If felodipine extended-release tablets are used during pregnancy, or if the patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus, possible digital anomalies of the infant, and the potential effects of felodipine on labor and delivery and on the mammary glands of pregnant females.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Felodipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Felodipine during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is secreted in human milk and because of the potential for serious adverse reactions from felodipine in the infant, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of felodipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Pharmacokinetics, however, indicate that the availability of felodipine is increased in older patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Felodipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Felodipine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Felodipine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Felodipine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Felodipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Felodipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
FDA package insert for felodipine contains no information regarding drug monitoring.
# IV Compatibility
There is limited information about the IV compatibility.
# Overdosage
- Oral doses of 240 mg/kg and 264 mg/kg in male and female mice, respectively, and 2390 mg/kg and 2250 mg/kg in male and female rats, respectively, caused significant lethality.
- In a suicide attempt, one patient took 150 mg felodipine together with 15 tablets each of atenolol and spironolactone and 20 tablets of nitrazepam. The patient's blood pressure and heart rate were normal on admission to hospital; he subsequently recovered without significant sequelae.
- Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly bradycardia.
- If severe hypotension occurs, symptomatic treatment should be instituted. The patient should be placed supine with the legs elevated. The administration of intravenous fluids may be useful to treat hypotensiondue to overdosage with calcium antagonists. In case of accompanying bradycardia, atropine (0.5−1 mg) should be administered intravenously. Sympathomimetic drugs may also be given if the physician feels they are warranted.
- It has not been established whether felodipine can be removed from the circulation by hemodialysis.
- To obtain up-to-date information about the treatment of overdose, consult your Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient.
# Pharmacology
## Mechanism of Action
- Felodipine is a member of the dihydropyridine class of calcium channel antagonists (calcium channel blockers). It reversibly competes with an itrendipine and/or other calcium channel blockers for dihydropyridine binding sites, blocks voltage-dependent Ca++ currents in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.
- In vitro studies show that the effects of felodipine on contractile processes are selective, with greater effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals.
- The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance in man, with a modest reflex increase in heart rate (see Cardiovascular Effects). With the exception of a mild diuretic effect seen in several animal species and man, the effects of felodipine are accounted for by its effects on peripheral vascular resistance.
## Structure
- Felodipine (felodipine) is a calcium antagonist (calcium channel blocker). Felodipine is a dihydropyridine derivative that is chemically described as ± ethyl methyl 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. Its empirical formula is C18H19Cl2NO4 and its structural formula is:
- Felodipine is a slightly yellowish, crystalline powder with a molecular weight of 384.26. It is insoluble in water and is freely soluble in dichloromethane and ethanol. Felodipine is a racemic mixture.
- Tablets felodipine provide extended release of felodipine. They are available as tablets containing 2.5 mg, 5 mg, or 10 mg of felodipine for oral administration. In addition to the active ingredient felodipine, the tablets contain the following inactive ingredients: Tablets felodipine 2.5 mg — hydroxypropyl cellulose, lactose, FD&C Blue 2, sodium stearyl fumarate, titanium dioxide, yellow iron oxide, and other ingredients. Tablets Felodipine 5 mg and 10 mg — cellulose, red and yellow oxide, lactose, polyethylene glycol, sodium stearyl fumarate, titanium dioxide, and other ingredients.
## Pharmacodynamics
- Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-pass metabolism. The systemic bioavailability of felodipine is approximately 20%. Mean peak concentrations following the administration of felodipine are reached in 2.5 to 5 hours. Both peak plasma concentration and the area under the plasma concentration time curve (AUC) increase linearly with doses up to 20 mg. Felodipine is greater than 99% bound to plasma proteins.
- Following intravenous administration, the plasma concentration of felodipine declined triexponentially with mean disposition half-lives of 4.8 minutes, 1.5 hours, and 9.1 hours. The mean contributions of the three individual phases to the overall AUC were 15, 40, and 45%, respectively, in the order of increasing t1/2.
- Following oral administration of the immediate-release formulation, the plasma level of felodipine also declined polyexponentially with a mean terminal t1/2 of 11 to 16 hours. The mean peak and trough steady-state plasma concentrations achieved after 10 mg of the immediate-release formulation given once a day to normal volunteers, were 20 and 0.5 nmol/L, respectively. The trough plasma concentration of felodipine in most individuals was substantially below the concentration needed to effect a half-maximal decline in blood pressure (EC50) [4−6 nmol/L for felodipine], thus precluding once-a-day dosing with the immediate-release formulation.
- Following administration of a 10-mg dose of felodipine, the extended-release formulation, to young, healthy volunteers, mean peak and trough steady-state plasma concentrations of felodipine were 7 and 2 nmol/L, respectively. Corresponding values in hypertensive patients (mean age 64) after a 20-mg dose of felodipine were 23 and 7 nmol/L. Since the EC50 for felodipine is 4 to 6 nmol/L, a 5- to 10-mg dose of felodipine in some patients, and a 20-mg dose in others, would be expected to provide an antihypertensive effect that persists for 24 hours.
- The systemic plasma clearance of felodipine in young healthy subjects is about 0.8 L/min, and the apparent volume of distribution is about 10 L/kg.
- Following an oral or intravenous dose of 14C-labeled felodipine in man, about 70% of the dose of radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact felodipine is recovered in the urine and feces (< 0.5%). Six metabolites, which account for 23% of the oral dose, have been identified; none has significant vasodilating activity.
- Following administration of felodipine to hypertensive patients, mean peak plasma concentrations at steady state are about 20% higher than after a single dose. Blood pressure response is correlated with plasma concentrations of felodipine.
- The bioavailability of felodipine is influenced by the presence of food. When administered either with a high fat or carbohydrate diet, Cmax is increased by approximately 60%; AUC is unchanged. When felodipine was administered after a light meal (orange juice, toast, and cereal), however, there is no effect on felodipine’s pharmacokinetics. The bioavailability of felodipine was increased approximately two-fold when taken with grapefruit juice. Orange juice does not appear to modify the kinetics of Felodipine. A similar finding has been seen with other dihydropyridine calcium antagonists, but to a lesser extent than that seen with felodipine.
Geriatric Use – Plasma concentrations of felodipine, after a single dose and at steady state, increase with age. Mean clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that of young volunteers (mean age 26). At steady state mean AUC for young patients was 39% of that for the elderly. Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young and the elderly.
Hepatic Dysfunction – In patients with hepatic disease, the clearance of felodipine was reduced to about 60% of that seen in normal young volunteers.
- Renal impairment does not alter the plasma concentration profile of felodipine; although higher concentrations of the metabolites are present in the plasma due to decreased urinary excretion, these are inactive.
- Animal studies have demonstrated that felodipine crosses the blood-brain barrier and the placenta.
## Pharmacokinetics
## Cardiovascular Effects
- Following administration of felodipine, a reduction in blood pressure generally occurs within 2 to 5 hours. During chronic administration, substantial blood pressure control lasts for 24 hours, with trough reductions in diastolic blood pressure approximately 40−50% of peak reductions. The antihypertensive effect is dose dependent and correlates with the plasma concentration of felodipine.
- A reflex increase in heart rate frequently occurs during the first week of therapy; this increase attenuates over time. Heart rate increases of 5−10 beats per minute may be seen during chronic dosing. The increase is inhibited by beta-blocking agents.
- The P-R interval of the ECG is not affected by felodipine when administered alone or in combination with a beta-blocking agent. Felodipine alone or in combination with a beta-blocking agent has been shown, in clinical and electrophysiologic studies, to have no significant effect on cardiac conduction (P-R, P-Q, and H-V intervals).
- In clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in this population.
## Renal/Endocrine Effects
- Renal vascular resistance is decreased by felodipine while glomerular filtration rate remains unchanged. Mild diuresis, natriuresis, and kaliuresis have been observed during the first week of therapy. No significant effects on serum electrolytes were observed during short- and long-term therapy.
- In clinical trials in patients with hypertension, increases in plasma noradrenaline levels have been observed.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year carcinogenicity study in rats fed felodipine at doses of 7.7, 23.1 or 69.3 mg/kg/day (up to 61 times1 the maximum recommended human dose on a mg/m2 basis), a dose-related increase in the incidence of benign interstitial cell tumors of the testes (Leydig cell tumors) was observed in treated male rats. These tumors were not observed in a similar study in mice at doses up to 138.6 mg/kg/day (61 times1 the maximum recommended human dose on a mg/m2 basis). Felodipine, at the doses employed in the 2-year rat study, has been shown to lower testicular testosterone and to produce a corresponding increase in serum luteinizing hormone in rats. The Leydig cell tumor development is possibly secondary to these hormonal effects which have not been observed in man.
- In this same rat study a dose-related increase in the incidence of focal squamous cell hyperplasia compared to control was observed in the esophageal groove of male and female rats in all dose groups. No other drug-related esophageal or gastric pathology was observed in the rats or with chronic administration in mice and dogs. The latter species, like man, has no anatomical structure comparable to the esophageal groove.
- Felodipine was not carcinogenic when fed to mice at doses up to 138.6 mg/kg/day (61 times1 the maximum recommended human dose on a mg/m2 basis) for periods of up to 80 weeks in males and 99 weeks in females.
- Felodipine did not display any mutagenic activity in vitro in the Ames microbial mutagenicity test or in the mouse lymphoma forward mutation assay. No clastogenic potential was seen in vivo in the mouse micronucleus test at oral doses up to 2500 mg/kg (1100 times1 the maximum recommended human dose on a mg/m2 basis) or in vitro in a human lymphocyte chromosome aberration assay.
- A fertility study in which male and female rats were administered doses of 3.8, 9.6 or 26.9 mg/kg/day (up to 24 times1 the maximum recommended human dose on a mg/m2basis) showed no significant effect of felodipine on reproductive performance.
# Clinical Studies
- Felodipine produces dose-related decreases in systolic and diastolic blood pressure as demonstrated in six placebo-controlled, dose response studies using either immediate-release or extended-release dosage forms. These studies enrolled over 800 patients on active treatment, at total daily doses ranging from 2.5 to 20 mg. In those studies felodipine was administered either as monotherapy or was added to beta blockers. The results of the 2 studies with felodipine given once daily as monotherapy are shown in the table below:
# How Supplied
- Felodipine Extended-Release Tablets, USP are available containing 2.5 mg, 5 mg or 10 mg of felodipine, USP.
- The 2.5 mg tablet is a yellow colored, circular shaped, biconvex, film coated tablet de-bossed with 'I31' on one side and plain on other side.
- They are available as follows:
- The 5 mg tablet is a light yellow colored, circular shaped, biconvex, film coated tablet de-bossed with 'I32' on one side and plain on other side.
- They are available as follows:
- The 10 mg tablet is a white colored, circular shaped, biconvex, film coated tablet de-bossed with 'I33' on one side and plain on other side.
- They are available as follows:
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
- Manufactured for:
- Heritage Pharmaceuticals Inc.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to take felodipine extended-release tablets whole and not to crush or chew the tablets. They should be told that mild gingival hyperplasia (gum swelling) has been reported. Good dental hygiene decreases its incidence and severity.
NOTE: As with many other drugs, certain advice to patients being treated with felodipine extended-release tablets are warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
# Precautions with Alcohol
Alcohol-Felodipine sandbox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Plendil
# Look-Alike Drug Names
Felodipine - Isordil[10]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/AGON_SR | |
a37892ed4d6df6e035a6972316d95a88fc846d94 | wikidoc | Evolocumab | Evolocumab
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# Overview
Evolocumab is a PCSK9 (proprotein convertase subtilisin kexin type9) inhibitor antibody that is FDA approved for the treatment of Primary Hyperlipidemia, Homozygous Familial Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia, or Clinical atherosclerotic cardiovascular disease (CVD).. Common adverse reactions include Nasopharyngitis, upper respiratory tract infection, Influenza, back pain, and injection site reactions..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Primary Hyperlipidemia
- Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).
### Homozygous Familial Hypercholesterolemia
- Evolocumab is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.
## Dosage forms and strengths
- Evolocumab is a sterile, clear to opalescent, colorless to pale yellow solution available as follows:
Injection: 140 mg/mL solution in a single-use profiled syringe.
Injection: 140 mg/mL solution in a single-use prefilled SureClick® auto injector.
Injection: 420 mg/3.5 mL solution in a single-use PushtronexTM system (on-body infusor with prefilled cartridge).
- Injection: 140 mg/mL solution in a single-use profiled syringe.
- Injection: 140 mg/mL solution in a single-use prefilled SureClick® auto injector.
- Injection: 420 mg/3.5 mL solution in a single-use PushtronexTM system (on-body infusor with prefilled cartridge).
## Off-Label Use and Dosage (Adult)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Evolocumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
- Evolocumab is contraindicated in patients with a history of a serious hypersensitivity reaction to Evolocumab.
# Warnings
### Allergic Reactions
- Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with Evolocumab, including some that led to discontinuation of therapy.
- If signs or symptoms of serious allergic reactions occur, discontinue treatment with Evolocumab, treat according to the standard of care, and monitor until signs and symptoms resolve.
# Adverse Reactions
## Clinical Trials Experience
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Adverse Reactions in Patients with Primary Hyperlipidemia and in Patients with Heterozygous Familial Hypercholesterolemia
- Evolocumab is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD.
- The data described below reflect exposure to Evolocumab in 8 placebo-controlled trials that included 2651 patients treated with Evolocumab, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks).
- The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races.
- Adverse Reactions in a 52-Week Controlled Trial
- In a 52-week, double-blind, randomized, placebo-controlled trial (Study 2), 599 patients received 420 mg of Evolocumab subcutaneously once monthly.
- The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian, and 6% Hispanic.
- Adverse reactions reported in at least 3% of Evolocumab-treated patients, and more frequently than in placebo-treated patients in Study 2, are shown in Table 1.
- Adverse reactions led to discontinuation of treatment in 2.2% of Evolocumab-treated patients and 1% of placebo-treated patients.
- The most common adverse reaction that led to Evolocumab treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for Evolocumab and placebo, respectively).
† includes erythema, pain, bruising.
- Adverse Reactions in Seven Pooled 12-Week Controlled Trials
- In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of Evolocumab subcutaneously every 2 weeks and 1059 patients received 420 mg of Evolocumab subcutaneously monthly.
- The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian, and 5% Hispanic.
- Adverse reactions reported in at least 1% of Evolocumab-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2.
- Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial)
- The adverse reactions described below are from a pool of the 52-week trial (Study 2) and seven 12-week trials.
- The mean and median exposure durations of Evolocumab in this pool of eight trials were 20 weeks and 12 weeks, respectively.
- Local Injection Site Reactions
- Injection site reactions occurred in 3.2% and 3.0% of Evolocumab-treated and placebo-treated patients, respectively.
- The most common injection site reactions were erythema, pain, and bruising.
- The proportions of patients who discontinued treatment due to local injection site reactions in Evolocumab-treated patients and placebo-treated patients were 0.1% and 0%, respectively.
- Allergic Reactions
- Allergic reactions occurred in 5.1% and 4.7% of Evolocumab-treated and placebo-treated patients, respectively.
- The most common allergic reactions were rash (1.0% versus 0.5% for Evolocumab and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).
- Neurocognitive Events
- In placebo-controlled trials, neurocognitive events were reported in less than or equal to 0.2% in Evolocumab-treated and placebo-treated patients.
- Low LDL-C Levels
- In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1988 patients treated with Evolocumab had at least one LDL-C value < 25 mg/dL.
- Changes to background lipid-altering therapy were not made in response to low LDL-C values, and Evolocumab dosing was not modified or interrupted on this basis.
- Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by Evolocumab are unknown.
- Musculoskeletal Events
- Musculoskeletal adverse reactions were reported in 14.3% of Evolocumab-treated patients and 12.8% of placebo-treated patients.
- The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for Evolocumab and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
- Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
- In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients received 420 mg of Evolocumab subcutaneously once monthly .
- The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other.
- The adverse reactions that occurred in at least two (6.1%) Evolocumab-treated patients, and more frequently than in placebo-treated patients, included:
- Upper respiratory tract infection(9.1% versus 6.3%).
Influenza (9.1% versus 0%).
Gastroenteritis (6.1% versus 0%).
Nasopharyngitis (6.1% versus 0%).
- Upper respiratory tract infection(9.1% versus 6.3%).
- Influenza (9.1% versus 0%).
- Gastroenteritis (6.1% versus 0%).
- Nasopharyngitis (6.1% versus 0%).
### Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity.
- The immunogenicity of Evolocumab has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies.
- For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
- In a pool of placebo- and active-controlled clinical trials, 0.1% of patients treated with at least one dose of Evolocumab tested positive for binding antibody development.
- Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.
- There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of Evolocumab, but the long-term consequences of continuing Evolocumab treatment in the presence of anti-drug binding antibodies are unknown.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
- Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
- For these reasons, comparison of the incidence of antibodies to Evolocumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Evolocumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Evolocumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
## Pregnancy
- Risk Summary
- There are no data available on use of Evolocumab in pregnant women to inform a drug-associated risk.
- In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month.
- In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses.
- The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically.
- No assessment for immune suppression was conducted with evolocumab in infant monkeys.
- Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier.
- FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester.
- Consider the benefits and risks of Evolocumab and possible risks to the fetus before prescribing Evolocumab to pregnant women.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- Data
- Animal Data
- In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- No test of humoral immunity in infant monkeys was conducted with evolocumab.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Evolocumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Evolocumab during labor and delivery.
### Nursing Mothers
## Lactation
- Risk Summary
- There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production.
- The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Evolocumab and any potential adverse effects on the breastfed infant from Evolocumab or from the underlying maternal condition.
- Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.
### Pediatric Use
## Pediatric Use
- The safety and effectiveness of Evolocumab in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents (ages 13 to 17 years old) with HoFH.
- In this trial, 7 adolescents received Evolocumab 420 mg subcutaneously once monthly and 3 adolescents received placebo.
- The effect of Evolocumab on LDL-C was generally similar to that observed among adult patients with HoFH.
- Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with Evolocumab, with a median exposure duration of 9 months.
- The safety profile of Evolocumab in these adolescents was similar to that described for adult patients with HoFH.
- The safety and effectiveness of Evolocumab have not been established in pediatric patients with HoFH who are younger than 13 years old.
- The safety and effectiveness of Evolocumab have not been established in pediatric patients with primary hyperlipidemia or HeFH.
### Geriatic Use
## Geriatric Use
- In controlled studies, 1420 patients treated with Evolocumab were ≥ 65 years old and 171 were ≥ 75 years old.
- No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Evolocumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Evolocumab with respect to specific racial populations.
### Renal Impairment
## Renal Impairment
- No dose adjustment is needed in patients with mild to moderate renal impairment. No data are available in patients with severe renal impairment.
### Hepatic Impairment
## Hepatic Impairment
- No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B).
- No data are available in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Evolocumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Evolocumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The 420 mg dose of Evolocumab can be administered:
- Provide proper training to patients and/or caregivers on how to prepare and administer Evolocumab prior to use, according to the Instructions for Use, including aseptic technique.
- Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use Evolocumab.
- Keep Evolocumab in the refrigerator.
- Prior to use, allow Evolocumab to warm to room temperature for at least 30 minutes for the single-use prefilled autoinjector or single-use prefilled syringe and for at least 45 minutes for the single-use on-body infusor with prefilled cartridge.
- Do not warm in any other way.
- Alternatively, for patients and caregivers, Evolocumab can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton.
- However, under these conditions, Evolocumab must be used within 30 days.
- Visually inspect Evolocumab for particles and discoloration prior to administration.
- Evolocumab is a clear to opalescent, colorless to pale yellow solution.
- Do not use if the solution is cloudy or discolored or contains particles.
- Administer Evolocumab subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe, single-use prefilled autoinjector, or single-use on-body infusor with prefilled cartridge.
- Do not co-administer Evolocumab with other injectable drugs at the same administration site.
- Rotate the site of each subcutaneous administration.
### Monitoring
- The recommended subcutaneous dosage of Evolocumab in patients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly.
- When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.
- The recommended subcutaneous dosage of Evolocumab in patients with HoFH is 420 mg once monthly.
- In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function.
- If an every 2 week or once monthly dose is missed, instruct the patient to:
Administer Evolocumab as soon as possible if there are more than 7 days until the next scheduled dose, or,
- Administer Evolocumab as soon as possible if there are more than 7 days until the next scheduled dose, or,
Omit the missed dose and administer the next dose according to the original schedule.
# IV Compatibility
There is limited information regarding the compatibility of Evolocumab and IV administrations.
# Overdosage
There is limited information regarding Evolocumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Evolocumab Pharmacology in the drug label.
## Mechanism of Action
- Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9).
- Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface.
- By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.
## Structure
- Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin 9 (PCSK9).
- Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
- Evolocumab is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous administration.
- Each 1 mL single-use prefilled syringe and single-use prefilled SureClick® autoinjector contains 140 mg evolocumab, acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in Water for Injection, USP.
- Sodium hydroxide may be used to adjust to a pH of 5.0.
- Each single-use PushtronexTM system (on-body infusor with prefilled cartridge) delivers a 3.5 mL solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in Water for Injection, USP.
- Sodium hydroxide may be used to adjust to a pH of 5.0.
## Pharmacodynamics
- Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours.
- Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.
## Pharmacokinetics
- Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9.
- Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation ) of 18.6 (7.3) μg/mL and AUClast mean (SD) of 188 (98.6) dayμg/mL.
- Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean (SD) of 59.0 (17.2) μg/mL and AUClast mean (SD) of 924 (346) dayμg/mL.
- Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr.
- An approximate 2- to 3-fold accumulation was observed in trough serum concentrations (Cmin 7.21 ) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin 11.2 ), and serum trough concentrations approached steady state by 12 weeks of dosing.
- Absorption
- Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%.
- Distribution
- Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L.
- Metabolism and Elimination
- Two elimination phases were observed for Evolocumab.
- At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of Evolocumab is largely through a non-saturable proteolytic pathway.
- Evolocumab was estimated to have an effective half-life of 11 to 17 days.
- Specific Populations
- The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance, across all approved populations .
- The exposure of evolocumab decreased with increasing body weight.
- These differences are not clinically meaningful.
- Renal Impairment
- Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab.
- Patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2) have not been studied.
- Hepatic Impairment
- Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients.
- Pregnancy
- The effect of pregnancy on evolocumab pharmacokinetics has not been studied.
- Drug Interaction Studies
- An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in patients co-administered with a high-intensity statin regimen.
- This difference is not clinically meaningful and does not impact dosing recommendations.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks.
- There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- The mutagenic potential of evolocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
- There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embryonic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks.
- The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- In addition, there were no adverse evolocumab-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly.
- The highest dose tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
### Animal Toxicology and/or Pharmacology
- During a 3-month toxicology study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin in adult monkeys, there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after 1 to 2 months exposure.
- The highest dose tested corresponds to exposures 54- and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- Similarly, there were no effects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
# Clinical Studies
## Clinical Studies
### Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease
- Study 1 was a multicenter, double-blind, randomized controlled trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of Evolocumab 140 mg every 2 weeks, Evolocumab 420 mg once monthly, or placebo for 12 weeks.
- The trial included 296 patients with atherosclerotic CVD who received Evolocumab or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg.
- Among these patients, the mean age at baseline was 63 years (range: 32 to 80 years), 45% were ≥ 65 years old, 33% women, 98% White, 2% were Black, < 1% Asian and 5% Hispanic or Latino.
- After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dL.
- In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between Evolocumab and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% (95% CI: -81%, -61%; p < 0.0001) and -63% (95% CI: -76%, -50%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 3 and Figure 1.
- Study 2 was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 139 patients with atherosclerotic CVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily.
- After stabilization on background therapy, patients were randomly assigned to the addition of placebo or Evolocumab 420 mg administered subcutaneously once monthly.
- Among these patients, the mean age at baseline was 59 years (range: 35 to 75 years), 25% were ≥ 65 years, 40% women, 80% White, 3% Black, 5% Asian, and < 1% Hispanic or Latino.
- After stabilization on the assigned background therapy, the mean baseline LDL-C was 105 mg/dL.
- In these patients with atherosclerotic CVD on maximum-dose atorvastatin therapy with or without ezetimibe, the difference between Evolocumab 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -54 % (95% CI: -65%, -42%; p ˂ 0.0001) (Table 4 and Figure 2).
- For additional results see Table 4.
### Heterozygous Familial Hypercholesterolemia (HeFH)
- Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies.
- Patients were randomized to receive subcutaneous injections of Evolocumab 140 mg every two weeks, 420 mg once monthly, or placebo.
- HeFH was diagnosed by the Simon Broome criteria (1991).
- In Study 3, 38% of patients had clinical atherosclerotic cardiovascular disease.
- The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black.
- The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy.
- In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (95% CI: -67%, -55%; p < 0.0001) and -60% (95% CI: -68%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively.
- For additional results see Table 5.
### Homozygous Familial Hypercholesterolemia (HoFH)
- Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia (HoFH).
- In this trial, 33 patients received subcutaneous injections of 420 mg of Evolocumab once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe).
- The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other.
- The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received Evolocumab.
- The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe.
- The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents.
- In these patients with HoFH, the difference between Evolocumab and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (95% CI: -44%, -18%; p < 0.0001).
- For additional results see Table 6.
- Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to Evolocumab.
# How Supplied
- Evolocumab is a sterile, clear to opalescent, colorless to pale yellow solution for subcutaneous administration supplied in a single-use prefilled syringe, a single-use prefilled SureClick® autoinjector, or a single-use PushtronexTM system (on-body infusor with prefilled cartridge).
- Each single-use prefilled syringe or single-use prefilled SureClick® autoinjector of Evolocumab is designed to deliver 1 mL of 140 mg/mL solution.
- Each single-use PushtronexTM system (on-body infusor with prefilled cartridge) is designed to deliver 420 mg evolocumab in 3.5 mL solution.
## Storage
There is limited information regarding Evolocumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling before the patient starts using Evolocumab, and each time the patient gets a refill as there may be new information they need to know.
- Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-use prefilled autoinjector, single-use prefilled syringe, or single-use on-body infusor with prefilled cartridge correctly (see Instructions for Use leaflet).
- Inform patients that it may take up to 15 seconds to administer Evolocumab using the single-use prefilled autoinjector or single-use prefilled syringe and about 9 minutes to administer Evolocumab using the single-use on-body infusor with prefilled cartridge.
- Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the glass single-use prefilled syringe and the single-use prefilled autoinjector.
- The single-use on-body infusor with prefilled cartridge is not made with natural rubber latex.
# Precautions with Alcohol
Alcohol-Evolocumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
REPATHA® (evolocumab)
# Look-Alike Drug Names
There is limited information regarding Evolocumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Evolocumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]
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# Overview
Evolocumab is a PCSK9 (proprotein convertase subtilisin kexin type9) inhibitor antibody that is FDA approved for the treatment of Primary Hyperlipidemia, Homozygous Familial Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia, or Clinical atherosclerotic cardiovascular disease (CVD).. Common adverse reactions include Nasopharyngitis, upper respiratory tract infection, Influenza, back pain, and injection site reactions..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Primary Hyperlipidemia
- Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of low density lipoprotein cholesterol (LDL-C).
### Homozygous Familial Hypercholesterolemia
- Evolocumab is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C.
## Dosage forms and strengths
- Evolocumab is a sterile, clear to opalescent, colorless to pale yellow solution available as follows:
Injection: 140 mg/mL solution in a single-use profiled syringe.
Injection: 140 mg/mL solution in a single-use prefilled SureClick® auto injector.
Injection: 420 mg/3.5 mL solution in a single-use PushtronexTM system (on-body infusor with prefilled cartridge).
- Injection: 140 mg/mL solution in a single-use profiled syringe.
- Injection: 140 mg/mL solution in a single-use prefilled SureClick® auto injector.
- Injection: 420 mg/3.5 mL solution in a single-use PushtronexTM system (on-body infusor with prefilled cartridge).
## Off-Label Use and Dosage (Adult)
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Evolocumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
# Contraindications
- Evolocumab is contraindicated in patients with a history of a serious hypersensitivity reaction to Evolocumab.
# Warnings
### Allergic Reactions
- Hypersensitivity reactions (e.g., rash, urticaria) have been reported in patients treated with Evolocumab, including some that led to discontinuation of therapy.
- If signs or symptoms of serious allergic reactions occur, discontinue treatment with Evolocumab, treat according to the standard of care, and monitor until signs and symptoms resolve.
# Adverse Reactions
## Clinical Trials Experience
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Adverse Reactions in Patients with Primary Hyperlipidemia and in Patients with Heterozygous Familial Hypercholesterolemia
- Evolocumab is not indicated for use in patients without familial hypercholesterolemia or atherosclerotic CVD.
- The data described below reflect exposure to Evolocumab in 8 placebo-controlled trials that included 2651 patients treated with Evolocumab, including 557 exposed for 6 months and 515 exposed for 1 year (median treatment duration of 12 weeks).
- The mean age of the population was 57 years, 49% of the population were women, 85% White, 6% Black, 8% Asians, and 2% other races.
- Adverse Reactions in a 52-Week Controlled Trial
- In a 52-week, double-blind, randomized, placebo-controlled trial (Study 2), 599 patients received 420 mg of Evolocumab subcutaneously once monthly.
- The mean age was 56 years (range: 22 to 75 years), 23% were older than 65 years, 52% women, 80% White, 8% Black, 6% Asian, and 6% Hispanic.
- Adverse reactions reported in at least 3% of Evolocumab-treated patients, and more frequently than in placebo-treated patients in Study 2, are shown in Table 1.
- Adverse reactions led to discontinuation of treatment in 2.2% of Evolocumab-treated patients and 1% of placebo-treated patients.
- The most common adverse reaction that led to Evolocumab treatment discontinuation and occurred at a rate greater than placebo was myalgia (0.3% versus 0% for Evolocumab and placebo, respectively).
† includes erythema, pain, bruising.
- Adverse Reactions in Seven Pooled 12-Week Controlled Trials
- In seven pooled 12-week, double-blind, randomized, placebo-controlled trials, 993 patients received 140 mg of Evolocumab subcutaneously every 2 weeks and 1059 patients received 420 mg of Evolocumab subcutaneously monthly.
- The mean age was 57 years (range: 18 to 80 years), 29% were older than 65 years, 49% women, 85% White, 5% Black, 9% Asian, and 5% Hispanic.
- Adverse reactions reported in at least 1% of Evolocumab-treated patients, and more frequently than in placebo-treated patients, are shown in Table 2.
- Adverse Reactions in Eight Pooled Controlled Trials (Seven 12-Week Trials and One 52-Week Trial)
- The adverse reactions described below are from a pool of the 52-week trial (Study 2) and seven 12-week trials.
- The mean and median exposure durations of Evolocumab in this pool of eight trials were 20 weeks and 12 weeks, respectively.
- Local Injection Site Reactions
- Injection site reactions occurred in 3.2% and 3.0% of Evolocumab-treated and placebo-treated patients, respectively.
- The most common injection site reactions were erythema, pain, and bruising.
- The proportions of patients who discontinued treatment due to local injection site reactions in Evolocumab-treated patients and placebo-treated patients were 0.1% and 0%, respectively.
- Allergic Reactions
- Allergic reactions occurred in 5.1% and 4.7% of Evolocumab-treated and placebo-treated patients, respectively.
- The most common allergic reactions were rash (1.0% versus 0.5% for Evolocumab and placebo, respectively), eczema (0.4% versus 0.2%), erythema (0.4% versus 0.2%), and urticaria (0.4% versus 0.1%).
- Neurocognitive Events
- In placebo-controlled trials, neurocognitive events were reported in less than or equal to 0.2% in Evolocumab-treated and placebo-treated patients.
- Low LDL-C Levels
- In a pool of placebo- and active-controlled trials, as well as open-label extension studies that followed them, a total of 1988 patients treated with Evolocumab had at least one LDL-C value < 25 mg/dL.
- Changes to background lipid-altering therapy were not made in response to low LDL-C values, and Evolocumab dosing was not modified or interrupted on this basis.
- Although adverse consequences of very low LDL-C were not identified in these trials, the long-term effects of very low levels of LDL-C induced by Evolocumab are unknown.
- Musculoskeletal Events
- Musculoskeletal adverse reactions were reported in 14.3% of Evolocumab-treated patients and 12.8% of placebo-treated patients.
- The most common adverse reactions that occurred at a rate greater than placebo were back pain (3.2% versus 2.9% for Evolocumab and placebo, respectively), arthralgia (2.3% versus 2.2%), and myalgia (2.0% versus 1.8%).
- Adverse Reactions in Patients with Homozygous Familial Hypercholesterolemia
- In a 12-week, double-blind, randomized, placebo-controlled trial of 49 patients with HoFH (Study 4), 33 patients received 420 mg of Evolocumab subcutaneously once monthly [see Clinical Studies (14.3)].
- The mean age was 31 years (range: 13 to 57 years), 49% were women, 90% White, 4% Asian, and 6% other.
- The adverse reactions that occurred in at least two (6.1%) Evolocumab-treated patients, and more frequently than in placebo-treated patients, included:
- Upper respiratory tract infection(9.1% versus 6.3%).
Influenza (9.1% versus 0%).
Gastroenteritis (6.1% versus 0%).
Nasopharyngitis (6.1% versus 0%).
- Upper respiratory tract infection(9.1% versus 6.3%).
- Influenza (9.1% versus 0%).
- Gastroenteritis (6.1% versus 0%).
- Nasopharyngitis (6.1% versus 0%).
### Immunogenicity
- As with all therapeutic proteins, there is potential for immunogenicity.
- The immunogenicity of Evolocumab has been evaluated using an electrochemiluminescent bridging screening immunoassay for the detection of binding anti-drug antibodies.
- For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
- In a pool of placebo- and active-controlled clinical trials, 0.1% of patients treated with at least one dose of Evolocumab tested positive for binding antibody development.
- Patients whose sera tested positive for binding antibodies were further evaluated for neutralizing antibodies; none of the patients tested positive for neutralizing antibodies.
- There was no evidence that the presence of anti-drug binding antibodies impacted the pharmacokinetic profile, clinical response, or safety of Evolocumab, but the long-term consequences of continuing Evolocumab treatment in the presence of anti-drug binding antibodies are unknown.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay.
- Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
- For these reasons, comparison of the incidence of antibodies to Evolocumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Evolocumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Evolocumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
## Pregnancy
- Risk Summary
- There are no data available on use of Evolocumab in pregnant women to inform a drug-associated risk.
- In animal reproduction studies, there were no effects on pregnancy or neonatal/infant development when monkeys were subcutaneously administered evolocumab from organogenesis through parturition at dose exposures up to 12 times the exposure at the maximum recommended human dose of 420 mg every month.
- In a similar study with another drug in the PCSK9 inhibitor antibody class, humoral immune suppression was observed in infant monkeys exposed to that drug in utero at all doses.
- The exposures where immune suppression occurred in infant monkeys were greater than those expected clinically.
- No assessment for immune suppression was conducted with evolocumab in infant monkeys.
- Measurable evolocumab serum concentrations were observed in the infant monkeys at birth at comparable levels to maternal serum, indicating that evolocumab, like other IgG antibodies, crosses the placental barrier.
- FDA’s experience with monoclonal antibodies in humans indicates that they are unlikely to cross the placenta in the first trimester; however, they are likely to cross the placenta in increasing amounts in the second and third trimester.
- Consider the benefits and risks of Evolocumab and possible risks to the fetus before prescribing Evolocumab to pregnant women.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
- Data
- Animal Data
- In cynomolgus monkeys, no effects on embryo-fetal or postnatal development (up to 6 months of age) were observed when evolocumab was dosed during organogenesis to parturition at 50 mg/kg once every 2 weeks by the subcutaneous route at exposures 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- No test of humoral immunity in infant monkeys was conducted with evolocumab.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Evolocumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Evolocumab during labor and delivery.
### Nursing Mothers
## Lactation
- Risk Summary
- There is no information regarding the presence of evolocumab in human milk, the effects on the breastfed infant, or the effects on milk production.
- The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Evolocumab and any potential adverse effects on the breastfed infant from Evolocumab or from the underlying maternal condition.
- Human IgG is present in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts.
### Pediatric Use
## Pediatric Use
- The safety and effectiveness of Evolocumab in combination with diet and other LDL-C-lowering therapies in adolescents with HoFH who require additional lowering of LDL-C were established based on data from a 12-week, placebo-controlled trial that included 10 adolescents (ages 13 to 17 years old) with HoFH.
- In this trial, 7 adolescents received Evolocumab 420 mg subcutaneously once monthly and 3 adolescents received placebo.
- The effect of Evolocumab on LDL-C was generally similar to that observed among adult patients with HoFH.
- Including experience from open-label, uncontrolled studies, a total of 14 adolescents with HoFH have been treated with Evolocumab, with a median exposure duration of 9 months.
- The safety profile of Evolocumab in these adolescents was similar to that described for adult patients with HoFH.
- The safety and effectiveness of Evolocumab have not been established in pediatric patients with HoFH who are younger than 13 years old.
- The safety and effectiveness of Evolocumab have not been established in pediatric patients with primary hyperlipidemia or HeFH.
### Geriatic Use
## Geriatric Use
- In controlled studies, 1420 patients treated with Evolocumab were ≥ 65 years old and 171 were ≥ 75 years old.
- No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
There is no FDA guidance on the use of Evolocumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Evolocumab with respect to specific racial populations.
### Renal Impairment
## Renal Impairment
- No dose adjustment is needed in patients with mild to moderate renal impairment. No data are available in patients with severe renal impairment.
### Hepatic Impairment
## Hepatic Impairment
- No dose adjustment is needed in patients with mild to moderate hepatic impairment (Child-Pugh A or B).
- No data are available in patients with severe hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Evolocumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Evolocumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The 420 mg dose of Evolocumab can be administered:
- Provide proper training to patients and/or caregivers on how to prepare and administer Evolocumab prior to use, according to the Instructions for Use, including aseptic technique.
- Instruct patients and/or caregivers to read and follow the Instructions for Use each time they use Evolocumab.
- Keep Evolocumab in the refrigerator.
- Prior to use, allow Evolocumab to warm to room temperature for at least 30 minutes for the single-use prefilled autoinjector or single-use prefilled syringe and for at least 45 minutes for the single-use on-body infusor with prefilled cartridge.
- Do not warm in any other way.
- Alternatively, for patients and caregivers, Evolocumab can be kept at room temperature at 68°F to 77°F (20°C to 25°C) in the original carton.
- However, under these conditions, Evolocumab must be used within 30 days.
- Visually inspect Evolocumab for particles and discoloration prior to administration.
- Evolocumab is a clear to opalescent, colorless to pale yellow solution.
- Do not use if the solution is cloudy or discolored or contains particles.
- Administer Evolocumab subcutaneously into areas of the abdomen, thigh, or upper arm that are not tender, bruised, red, or indurated using a single-use prefilled syringe, single-use prefilled autoinjector, or single-use on-body infusor with prefilled cartridge.
- Do not co-administer Evolocumab with other injectable drugs at the same administration site.
- Rotate the site of each subcutaneous administration.
### Monitoring
- The recommended subcutaneous dosage of Evolocumab in patients with HeFH or patients with primary hyperlipidemia with established clinical atherosclerotic CVD is either 140 mg every 2 weeks OR 420 mg once monthly.
- When switching dosage regimens, administer the first dose of the new regimen on the next scheduled date of the prior regimen.
- The recommended subcutaneous dosage of Evolocumab in patients with HoFH is 420 mg once monthly.
- In patients with HoFH, measure LDL-C levels 4 to 8 weeks after starting REPATHA, since response to therapy will depend on the degree of LDL-receptor function.
- If an every 2 week or once monthly dose is missed, instruct the patient to:
Administer Evolocumab as soon as possible if there are more than 7 days until the next scheduled dose, or,
- Administer Evolocumab as soon as possible if there are more than 7 days until the next scheduled dose, or,
Omit the missed dose and administer the next dose according to the original schedule.
# IV Compatibility
There is limited information regarding the compatibility of Evolocumab and IV administrations.
# Overdosage
There is limited information regarding Evolocumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Evolocumab Pharmacology in the drug label.
## Mechanism of Action
- Evolocumab is a human monoclonal IgG2 directed against human proprotein convertase subtilisin kexin 9 (PCSK9).
- Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface.
- By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.
## Structure
- Evolocumab is a human monoclonal immunoglobulin G2 (IgG2) directed against human proprotein convertase subtilisin kexin 9 (PCSK9).
- Evolocumab has an approximate molecular weight (MW) of 144 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.
- Evolocumab is a sterile, preservative-free, clear to opalescent, colorless to pale yellow solution for subcutaneous administration.
- Each 1 mL single-use prefilled syringe and single-use prefilled SureClick® autoinjector contains 140 mg evolocumab, acetate (1.2 mg), polysorbate 80 (0.1 mg), proline (25 mg) in Water for Injection, USP.
- Sodium hydroxide may be used to adjust to a pH of 5.0.
- Each single-use PushtronexTM system (on-body infusor with prefilled cartridge) delivers a 3.5 mL solution containing 420 mg evolocumab, acetate (4.2 mg), polysorbate 80 (0.35 mg), proline (89 mg) in Water for Injection, USP.
- Sodium hydroxide may be used to adjust to a pH of 5.0.
## Pharmacodynamics
- Following single subcutaneous administration of 140 mg or 420 mg of evolocumab, maximum suppression of circulating unbound PCSK9 occurred by 4 hours.
- Unbound PCSK9 concentrations returned toward baseline when evolocumab concentrations decreased below the limit of quantitation.
## Pharmacokinetics
- Evolocumab exhibits non-linear kinetics as a result of binding to PCSK9.
- Administration of the 140 mg dose in healthy volunteers resulted in a Cmax mean (standard deviation [SD]) of 18.6 (7.3) μg/mL and AUClast mean (SD) of 188 (98.6) day•μg/mL.
- Administration of the 420 mg dose in healthy volunteers resulted in a Cmax mean (SD) of 59.0 (17.2) μg/mL and AUClast mean (SD) of 924 (346) day•μg/mL.
- Following a single 420 mg intravenous dose, the mean (SD) systemic clearance was estimated to be 12 (2) mL/hr.
- An approximate 2- to 3-fold accumulation was observed in trough serum concentrations (Cmin [SD] 7.21 [6.6]) following 140 mg doses administered subcutaneously every 2 weeks or following 420 mg doses administered subcutaneously monthly (Cmin [SD] 11.2 [10.8]), and serum trough concentrations approached steady state by 12 weeks of dosing.
- Absorption
- Following a single subcutaneous dose of 140 mg or 420 mg evolocumab administered to healthy adults, median peak serum concentrations were attained in 3 to 4 days, and estimated absolute bioavailability was 72%.
- Distribution
- Following a single 420 mg intravenous dose, the mean (SD) steady-state volume of distribution was estimated to be 3.3 (0.5) L.
- Metabolism and Elimination
- Two elimination phases were observed for Evolocumab.
- At low concentrations, the elimination is predominately through saturable binding to target (PCSK9), while at higher concentrations the elimination of Evolocumab is largely through a non-saturable proteolytic pathway.
- Evolocumab was estimated to have an effective half-life of 11 to 17 days.
- Specific Populations
- The pharmacokinetics of evolocumab were not affected by age, gender, race, or creatinine clearance, across all approved populations [see Use in Specific Populations (8.5)].
- The exposure of evolocumab decreased with increasing body weight.
- These differences are not clinically meaningful.
- Renal Impairment
- Since monoclonal antibodies are not known to be eliminated via renal pathways, renal function is not expected to impact the pharmacokinetics of evolocumab.
- Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) have not been studied.
- Hepatic Impairment
- Following a single 140 mg subcutaneous dose of evolocumab in patients with mild or moderate hepatic impairment, a 20-30% lower mean Cmax and 40-50% lower mean AUC were observed as compared to healthy patients; however, no dose adjustment is necessary in these patients.
- Pregnancy
- The effect of pregnancy on evolocumab pharmacokinetics has not been studied.
- Drug Interaction Studies
- An approximately 20% decrease in the Cmax and AUC of evolocumab was observed in patients co-administered with a high-intensity statin regimen.
- This difference is not clinically meaningful and does not impact dosing recommendations.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- The carcinogenic potential of evolocumab was evaluated in a lifetime study conducted in the hamster at dose levels of 10, 30, and 100 mg/kg administered every 2 weeks.
- There were no evolocumab-related tumors at the highest dose at systemic exposures up to 38- and 15-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- The mutagenic potential of evolocumab has not been evaluated; however, monoclonal antibodies are not expected to alter DNA or chromosomes.
- There were no adverse effects on fertility (including estrous cycling, sperm analysis, mating performance, and embryonic development) at the highest dose in a fertility and early embryonic developmental toxicology study in hamsters when evolocumab was subcutaneously administered at 10, 30, and 100 mg/kg every 2 weeks.
- The highest dose tested corresponds to systemic exposures up to 30- and 12-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- In addition, there were no adverse evolocumab-related effects on surrogate markers of fertility (reproductive organ histopathology, menstrual cycling, or sperm parameters) in a 6-month chronic toxicology study in sexually mature monkeys subcutaneously administered evolocumab at 3, 30, and 300 mg/kg once weekly.
- The highest dose tested corresponds to 744- and 300-fold the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
### Animal Toxicology and/or Pharmacology
- During a 3-month toxicology study of 10 and 100 mg/kg once every 2 weeks evolocumab in combination with 5 mg/kg once daily rosuvastatin in adult monkeys, there were no effects of evolocumab on the humoral immune response to keyhole limpet hemocyanin (KLH) after 1 to 2 months exposure.
- The highest dose tested corresponds to exposures 54- and 21-fold higher than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
- Similarly, there were no effects of evolocumab on the humoral immune response to KLH (after 3 to 4 months exposure) in a 6-month study in cynomolgus monkeys at dose levels up to 300 mg/kg once weekly evolocumab corresponding to exposures 744- and 300-fold greater than the recommended human doses of 140 mg every 2 weeks and 420 mg once monthly, respectively, based on plasma AUC.
# Clinical Studies
## Clinical Studies
### Primary Hyperlipidemia in Patients with Clinical Atherosclerotic Cardiovascular Disease
- Study 1 was a multicenter, double-blind, randomized controlled trial in which patients were initially randomized to an open-label specific statin regimen for a 4-week lipid stabilization period followed by random assignment to subcutaneous injections of Evolocumab 140 mg every 2 weeks, Evolocumab 420 mg once monthly, or placebo for 12 weeks.
- The trial included 296 patients with atherosclerotic CVD who received Evolocumab or placebo as add-on therapy to daily doses of atorvastatin 80 mg, rosuvastatin 40 mg, or simvastatin 40 mg.
- Among these patients, the mean age at baseline was 63 years (range: 32 to 80 years), 45% were ≥ 65 years old, 33% women, 98% White, 2% were Black, < 1% Asian and 5% Hispanic or Latino.
- After 4 weeks of statin therapy, the mean baseline LDL-C was 108 mg/dL.
- In these patients with atherosclerotic CVD who were on maximum-dose statin therapy, the difference between Evolocumab and placebo in mean percent change in LDL-C from baseline to Week 12 was -71% (95% CI: -81%, -61%; p < 0.0001) and -63% (95% CI: -76%, -50%; p ˂ 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively. For additional results see Table 3 and Figure 1.
- Study 2 was a multicenter, double-blind, randomized, placebo-controlled, 52-week trial that included 139 patients with atherosclerotic CVD who received protocol-determined background lipid-lowering therapy of atorvastatin 80 mg daily with or without ezetimibe 10 mg daily.
- After stabilization on background therapy, patients were randomly assigned to the addition of placebo or Evolocumab 420 mg administered subcutaneously once monthly.
- Among these patients, the mean age at baseline was 59 years (range: 35 to 75 years), 25% were ≥ 65 years, 40% women, 80% White, 3% Black, 5% Asian, and < 1% Hispanic or Latino.
- After stabilization on the assigned background therapy, the mean baseline LDL-C was 105 mg/dL.
- In these patients with atherosclerotic CVD on maximum-dose atorvastatin therapy with or without ezetimibe, the difference between Evolocumab 420 mg once monthly and placebo in mean percent change in LDL-C from baseline to Week 52 was -54 % (95% CI: -65%, -42%; p ˂ 0.0001) (Table 4 and Figure 2).
- For additional results see Table 4.
### Heterozygous Familial Hypercholesterolemia (HeFH)
- Study 3 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 329 patients with heterozygous familial hypercholesterolemia (HeFH) on statins with or without other lipid-lowering therapies.
- Patients were randomized to receive subcutaneous injections of Evolocumab 140 mg every two weeks, 420 mg once monthly, or placebo.
- HeFH was diagnosed by the Simon Broome criteria (1991).
- In Study 3, 38% of patients had clinical atherosclerotic cardiovascular disease.
- The mean age at baseline was 51 years (range: 19 to 79 years), 15% of the patients were ≥ 65 years old, 42% were women, 90% were White, 5% were Asian, and 1% were Black.
- The average LDL-C at baseline was 156 mg/dL with 76% of the patients on high-intensity statin therapy.
- In these patients with HeFH on statins with or without other lipid lowering therapies, the differences between REPATHA and placebo in mean percent change in LDL-C from baseline to Week 12 was -61% (95% CI: -67%, -55%; p < 0.0001) and -60% (95% CI: -68%, -52%; p < 0.0001) for the 140 mg every 2 weeks and 420 mg once monthly dosages, respectively.
- For additional results see Table 5.
### Homozygous Familial Hypercholesterolemia (HoFH)
- Study 4 was a multicenter, double-blind, randomized, placebo-controlled, 12-week trial in 49 patients (not on lipid-apheresis therapy) with homozygous familial hypercholesterolemia (HoFH).
- In this trial, 33 patients received subcutaneous injections of 420 mg of Evolocumab once monthly and 16 patients received placebo as an adjunct to other lipid-lowering therapies (e.g., statins, ezetimibe).
- The mean age at baseline was 31 years, 49% were women, 90% White, 4% were Asian, and 6% other.
- The trial included 10 adolescents (ages 13 to 17 years), 7 of whom received Evolocumab.
- The mean LDL-C at baseline was 349 mg/dL with all patients on statins (atorvastatin or rosuvastatin) and 92% on ezetimibe.
- The diagnosis of HoFH was made by genetic confirmation or a clinical diagnosis based on a history of an untreated LDL-C concentration > 500 mg/dL together with either xanthoma before 10 years of age or evidence of HeFH in both parents.
- In these patients with HoFH, the difference between Evolocumab and placebo in mean percent change in LDL-C from baseline to Week 12 was -31% (95% CI: -44%, -18%; p < 0.0001).
- For additional results see Table 6.
- Patients known to have two LDL-receptor negative alleles (little to no residual function) did not respond to Evolocumab.
# How Supplied
- Evolocumab is a sterile, clear to opalescent, colorless to pale yellow solution for subcutaneous administration supplied in a single-use prefilled syringe, a single-use prefilled SureClick® autoinjector, or a single-use PushtronexTM system (on-body infusor with prefilled cartridge).
- Each single-use prefilled syringe or single-use prefilled SureClick® autoinjector of Evolocumab is designed to deliver 1 mL of 140 mg/mL solution.
- Each single-use PushtronexTM system (on-body infusor with prefilled cartridge) is designed to deliver 420 mg evolocumab in 3.5 mL solution.
## Storage
There is limited information regarding Evolocumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling [Patient Information and Instructions for Use (IFU)] before the patient starts using Evolocumab, and each time the patient gets a refill as there may be new information they need to know.
- Provide guidance to patients and caregivers on proper subcutaneous administration technique, including aseptic technique, and how to use the single-use prefilled autoinjector, single-use prefilled syringe, or single-use on-body infusor with prefilled cartridge correctly (see Instructions for Use leaflet).
- Inform patients that it may take up to 15 seconds to administer Evolocumab using the single-use prefilled autoinjector or single-use prefilled syringe and about 9 minutes to administer Evolocumab using the single-use on-body infusor with prefilled cartridge.
- Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the glass single-use prefilled syringe and the single-use prefilled autoinjector.
- The single-use on-body infusor with prefilled cartridge is not made with natural rubber latex.
# Precautions with Alcohol
Alcohol-Evolocumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
REPATHA® (evolocumab)
# Look-Alike Drug Names
There is limited information regarding Evolocumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/AMG145 | |
8d0361dc0492431aa1e0c81ec9ceb7e26b5b9030 | wikidoc | APC (gene) | APC (gene)
# Overview
APC (adenomatosis polyposis coli) is a human gene that is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, or whether a cell moves within or away from a tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.
The APC gene is located on the long (q) arm of chromosome 5 between positions 21 and 22, from base pair 112,118,468 to base pair 112,209,532.
# Related conditions
Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene. More than 800 mutations in the APC gene have been identified in families with classic and attenuated types of familial adenomatous polyposis. Most of these mutations cause the production of an APC protein that is abnormally short and nonfunctional. This short protein cannot suppress the cellular overgrowth that leads to the formation of polyps, which can become cancerous. The most common mutation in familial adenomatous polyposis is a deletion of five bases (the building blocks of DNA) in the APC gene. This mutation changes the sequence of amino acids (the building material of proteins) in the resulting APC protein beginning at position 1309.
Another mutation is carried by approximately 6 percent of people of Ashkenazi (eastern and central European) Jewish heritage. This mutation results in the substitution of the amino acid lysine for isoleucine at position 1307 in the APC protein (also written as I1307K or Ile1307Lys). This change was initially thought to be harmless, but has recently been shown to be associated with a 10 to 20 percent increased risk of colon cancer.
# Regulation of Proliferation
The (Adenomatosis Polyposis Coli) APC protein normally builds a complex with glycogensynthasekinase 3beta(GSK 3β) and Axin. This complex is then able to bind β- catenins in the cytoplasm, that have dissociated from adherens contacts between cells. After binding, APC facilitates the lysis of this molecule through proteolytic enzymes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes. The deactivation of the APC protein can take place after certain chain reactions in the cytoplasm are started, e.g. through the Wnt signals that destroy the conformation of the complex. In the nucleus it complexes with legless/BCL9, TCF, and Pygo and begins function of an RNA polymerase but for oncogenes.
# Further reading
- Cohen MM Jr (2003). "Molecular dimensions of gastrointestinal tumors: some thoughts for digestion". Am J Med Genet A. 122 (4): 303–14..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} PMID 14518068
- Fearnhead NS, Britton MP, Bodmer WF (2001). "The ABC of APC". Hum Mol Genet. 10 (7): 721–33.CS1 maint: Multiple names: authors list (link) PMID 11257105
- Fodde R (2002). "The APC gene in colorectal cancer". Eur J Cancer. 38 (7): 867–71. PMID 11978510
- Goss KH, Groden J (2000). "Biology of the adenomatous polyposis coli tumor suppressor". J Clin Oncol. 18 (9): 1967–79. PMID 10784639
- Jarvinen HJ, Peltomaki P (2004). "The complex genotype-phenotype relationship in familial adenomatous polyposis". Eur J Gastroenterol Hepatol. 16 (1): 5–8. PMID 15095846
- Lal G, Gallinger S (2000). "Familial adenomatous polyposis". Semin Surg Oncol. 18 (4): 314–23. PMID 10805953
- van Es JH, Giles RH, Clevers HC (2001). "The many faces of the tumor suppressor gene APC". Exp Cell Res. 264 (1): 126–34.CS1 maint: Multiple names: authors list (link) PMID 11237529 | APC (gene)
# Overview
APC (adenomatosis polyposis coli) is a human gene that is classified as a tumor suppressor gene. Tumor suppressor genes prevent the uncontrolled growth of cells that may result in cancerous tumors. The protein made by the APC gene plays a critical role in several cellular processes that determine whether a cell may develop into a tumor. The APC protein helps control how often a cell divides, how it attaches to other cells within a tissue, or whether a cell moves within or away from a tissue. This protein also helps ensure that the chromosome number in cells produced through cell division is correct. The APC protein accomplishes these tasks mainly through association with other proteins, especially those that are involved in cell attachment and signaling. The activity of one protein in particular, beta-catenin, is controlled by the APC protein (see: Wnt signaling pathway). Regulation of beta-catenin prevents genes that stimulate cell division from being turned on too often and prevents cell overgrowth.
The APC gene is located on the long (q) arm of chromosome 5 between positions 21 and 22, from base pair 112,118,468 to base pair 112,209,532.
# Related conditions
Familial adenomatous polyposis (FAP) is caused by mutations in the APC gene. More than 800 mutations in the APC gene have been identified in families with classic and attenuated types of familial adenomatous polyposis. Most of these mutations cause the production of an APC protein that is abnormally short and nonfunctional. This short protein cannot suppress the cellular overgrowth that leads to the formation of polyps, which can become cancerous. The most common mutation in familial adenomatous polyposis is a deletion of five bases (the building blocks of DNA) in the APC gene. This mutation changes the sequence of amino acids (the building material of proteins) in the resulting APC protein beginning at position 1309.
Another mutation is carried by approximately 6 percent of people of Ashkenazi (eastern and central European) Jewish heritage. This mutation results in the substitution of the amino acid lysine for isoleucine at position 1307 in the APC protein (also written as I1307K or Ile1307Lys). This change was initially thought to be harmless, but has recently been shown to be associated with a 10 to 20 percent increased risk of colon cancer.
# Regulation of Proliferation
The (Adenomatosis Polyposis Coli) APC protein normally builds a complex with glycogensynthasekinase 3beta(GSK 3β) and Axin. This complex is then able to bind β- catenins in the cytoplasm, that have dissociated from adherens contacts between cells. After binding, APC facilitates the lysis of this molecule through proteolytic enzymes. This prevents it from translocating into the nucleus, where it acts as a transcription factor for proliferation genes. The deactivation of the APC protein can take place after certain chain reactions in the cytoplasm are started, e.g. through the Wnt signals that destroy the conformation of the complex. In the nucleus it complexes with legless/BCL9, TCF, and Pygo and begins function of an RNA polymerase but for oncogenes.
# Further reading
- Cohen MM Jr (2003). "Molecular dimensions of gastrointestinal tumors: some thoughts for digestion". Am J Med Genet A. 122 (4): 303–14..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} PMID 14518068
- Fearnhead NS, Britton MP, Bodmer WF (2001). "The ABC of APC". Hum Mol Genet. 10 (7): 721–33.CS1 maint: Multiple names: authors list (link) PMID 11257105
- Fodde R (2002). "The APC gene in colorectal cancer". Eur J Cancer. 38 (7): 867–71. PMID 11978510
- Goss KH, Groden J (2000). "Biology of the adenomatous polyposis coli tumor suppressor". J Clin Oncol. 18 (9): 1967–79. PMID 10784639
- Jarvinen HJ, Peltomaki P (2004). "The complex genotype-phenotype relationship in familial adenomatous polyposis". Eur J Gastroenterol Hepatol. 16 (1): 5–8. PMID 15095846
- Lal G, Gallinger S (2000). "Familial adenomatous polyposis". Semin Surg Oncol. 18 (4): 314–23. PMID 10805953
- van Es JH, Giles RH, Clevers HC (2001). "The many faces of the tumor suppressor gene APC". Exp Cell Res. 264 (1): 126–34.CS1 maint: Multiple names: authors list (link) PMID 11237529
# External links
- Adenomatous+Polyposis+Coli+Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
- GeneCard
de:APC (Gen)
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/APC_(gene) | |
45e4a302538ca9032f51d3d2a2b8d951d0813331 | wikidoc | Atazanavir | Atazanavir
- Content
- Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens. The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.
- Dosage Adjustments in Pregnant Patients
- Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults).
- Renal Impairment
- For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
- Dosage Adjustments in Patients with Hepatic Impairment
- Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.
- Dosage of REYATAZ Capsules in Pediatric Patients
The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).
- Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients
- REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 10 kg and less than 25 kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.
- Instructions for Mixing REYATAZ Oral Powder
- It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.
- Determine the number of packets (4 or 5 packets) that are needed.
- Prior to mixing, tap the packet to settle the powder. Use a clean pair of scissors to cut each packet along the dotted line.
- Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.
- Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.
- Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.
- Administer ritonavir immediately following REYATAZ powder administration.
- Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation (may leave the mixture at room temperature during this one hour period). Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.
- in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder.
- when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
- when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6).
- Table 6 displays drugs that are contraindicated with REYATAZ.
- Cardiac Conduction Abnormalities
- REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block). ECG monitoring should be considered in these patients.
- Rash
- In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in patients receiving REYATAZ. REYATAZ should be discontinued if severe rash develops.
- Hyperbilirubinemia
- Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established.
- Patients with Phenylketonuria
- Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.
- Hepatotoxicity
- Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment.
- Nephrolithiasis and Cholelithiasis
- Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving REYATAZ therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered.
- Diabetes Mellitus/Hyperglycemia
- New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Fat Redistribution
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Hemophilia
- There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
- Resistance/Cross-Resistance
- Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors.
- The safety profile of REYATAZ in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received REYATAZ 300 mg with ritonavir 100 mg and 1089 patients received REYATAZ 400 mg or higher (without ritonavir).
- The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.
- Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-naive patients receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.
- The safety profile of REYATAZ in treatment-experienced adults is based on 119 HIV-1 infected patients in clinical trials.
- The most common adverse reactions are jaundice/scleral icterus and myalgia.
- Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced patients receiving REYATAZ/ritonavir are presented in Table 9.
- Laboratory Abnormalities in Treatment-Naive Patients
- The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities are presented in Tables 10 and 11, respectively.
- Laboratory Abnormalities in Treatment-Experienced Patients
- The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3–4 laboratory abnormalities are presented in Table 12.
- Lipids, Change from Baseline in Treatment-Naive Patients
- For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 13 and 14, respectively.
- Lipids, Change from Baseline in Treatment-Experienced Patients
- For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.
- The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.
- The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric patients were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of patients. The most common Grade 3–4 laboratory abnormalities occurring in pediatric patients taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.
- The data described below reflect exposure to REYATAZ oral powder in 89 subjects weighing from 10 kg to less than 25 kg, including 65 patients exposed for 48 weeks. These data are from two pooled open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric patients (AI424-397 and AI424-451 ). Age ranged from 15 months to less than 7.5 years of age. In these studies 53% were female and 47% were male. All patients received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).
- The safety profile of REYATAZ in pediatric patients taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric patients weighing 10 kg to less than 25 kg taking REYATAZ oral powder were increased amylase (19%), neutropenia (12%), increased SGPT/ALT (5%), elevation of total bilirubin (≥2.6 times ULN, 12%), increased lipase (5%), and decreased hemoglobin (3%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.
- In study AI424-138, 60 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the REYATAZ/ritonavir-treated patients and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (6/60) of the REYATAZ/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.
- In study AI424-045, 20 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.
- In studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the REYATAZ-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels >5 times ULN developed in 9% of the REYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients.
- Body as a Whole: edema
- Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation
- Gastrointestinal System: pancreatitis
- Hepatic System: hepatic function abnormalities
- Hepatobiliary Disorders: cholelithiasis, cholecystitis, cholestasis
- Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia
- Musculoskeletal System: arthralgia
- Renal System: nephrolithiasis, interstitial nephritis
- Skin and Appendages: alopecia, maculopapular rash, pruritus, angioedema
- Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.
- Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.
- The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir.
- Potential for Other Drugs to Affect REYATAZ
- Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect.
- Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with REYATAZ.
- Established and Other Potentially Significant Drug Interactions
- Table 16 provides dosing recommendations as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
- Drugs with No Observed or Predicted Interactions with REYATAZ
- Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8.
- Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, or atenolol.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- Risk Summary
- Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.
- Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.
- Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women. All infants, including neonates exposed to REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.
- Clinical Considerations
- Dosing During Pregnancy and the Postpartum Period:
- REYATAZ should not be administered without ritonavir.
- REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
- For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions:
For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
- For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
- No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
- Human Data
- Clinical Trials: In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.
- Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.
- Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).
- Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
- Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.
- Animal Data
- In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atazanavir in women who are pregnant.
- The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 10 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397. The safety profile in pediatric patients was generally similar to that observed in adults.
## Signs and Symptoms
- Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in an HIV-infected patient (73 times the 400‑mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed.
## Management
- Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
# Chronic Overdose
There is limited information regarding Chronic Overdose of Atazanavir in the drug label.
- The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:
- Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C.
- REYATAZ Capsules are available for oral administration in strengths of 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir sulfate, respectively.The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.
- REYATAZ oral powder comes in a packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor.
- Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram.
- Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec.
- Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.
- Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Patients
- Absorption
- Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.
- Food Effect
- Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.
- Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.
- Distribution
- Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.
- Metabolism
- Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.
- Elimination
- Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
- Specific Populations
- Renal Impairment
- In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender‑matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
- Hepatic Impairment
- REYATAZ has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment.
- Pediatrics
- The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the powder formulation are summarized in Table 18 by weight ranges that correspond to the recommended doses.
- The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses.
- Pregnancy
- The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules with ritonavir are presented in Table 20.
- Drug Interaction Data
- Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM).
- Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.
- Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22.
- Mechanism of Action
- Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
- Antiviral Activity in Cell Culture
- Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.
- Resistance
- In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.
- Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted REYATAZ vs. Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs. REYATAZ 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.
- Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.
- Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.
- Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.
- Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451(PRINCE II): No treatment-emergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other PIs arose in the viruses from one subject each (L19I/R, M36M/I, H69K/R, and I72I/V). None of these viruses acquired phenotypic resistance to ATV, ATV/RTV, or any NNRTI or NRTI. In AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/I, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold change: 1.74, using a commercial investigational assay with an ATV cutoff of 2.2 fold change). Secondary PI substitutions also arose in the viruses of one subject each, including V11V/I, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61/E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from three subjects developed M184V in the reverse transcriptase, and all three exhibited phenotypic resistance to emtricitabine and lamivudine.
- Cross-Resistance
- Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.
- Baseline Genotype/Phenotype and Virologic Outcome Analyses
- Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 24.
- Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to patients with 1–2 PI substitutions, including one of these substitutions.
- The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.
- Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.
- Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).
- At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.
- Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of REYATAZ/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 was a 96-week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range: 19-72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26.
- Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the REYATAZ/ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm.
- Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + zidovudine twice daily. Study AI424-034 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27.
- Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm.
- Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients. Patients had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28.
- Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm.
- Adult Patients with Prior Antiretroviral Therapy
- Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 was a randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL).
- Treatment outcomes through Week 48 for the REYATAZ/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of quantification.
- No patients in the REYATAZ/ritonavir treatment arm and three patients in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.
- In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy.
- Study AI424-045 also compared changes from baseline in lipid values.
- Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log10 copies/mL in the REYATAZ treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.
- Pediatric Patients
- Pediatric Trials with REYATAZ Capsules
- Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs.
- One-hundred five (105) patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive patients and 220 cells/mm3 in antiretroviral-experienced patients.
- Pediatric Trials with REYATAZ Oral Powder
- Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.
AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age
- AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
- AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age
- In these studies 134 patients (73 antiretroviral-naive and 61 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.
- For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.
- Sixty-five (65) patients from both studies weighing 10 kg to less than 25 kg treated with REYATAZ oral powder with ritonavir were evaluated. Patients 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution, and patients 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <400 copies/mL at Week 48 were 78% (32/41) and 71% (17/24), respectively in patients who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively in patients who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy was 412 cells/mm3 (10.5%) in antiretroviral-naive patients and 228 cells/mm3 (6%) in antiretroviral-experienced patients who received REYATAZ oral powder with ritonavir.
- REYATAZ® (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.
- Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
- REYATAZ Oral Powder
- REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each.
- Store REYATAZ oral powder below 30°C (86°F). Once the REYATAZ oral powder is mixed with food or beverage, it may be kept at room temperature 20°C to 30°C (68°F-86°F) for up to 1 hour prior to administration. Store REYATAZ oral powder in the original packet and do not open until ready to use.
- REYATAZ is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a healthcare provider when using REYATAZ.
- Patients should be advised to avoid doing things that can spread HIV infection to others.
- Do not share or re-use needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. It is not known if REYATAZ can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV should not breastfeed because HIV can be passed to the baby in breast milk.
- Dosing Instructions
- Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a healthcare provider while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
- REYATAZ oral powder is available for pediatric patients who are 3 months and older weighing 10 kg to less than 25 kg. Caregivers should be advised on how to mix the REYATAZ oral powder with a food or beverage such as milk or water for infants and young children who can take solid foods or drink liquids from a cup. For infants who cannot take solid food or drink from a cup, the powder formulation mixed in liquid infant formula should be given with an oral dosing syringe. Caregivers should carefully follow the Instructions for Use and storage of the powder.
- Caregivers of patients with phenylketonuria should be advised that REYATAZ oral powder contains phenylalanine.
- Patients or caregivers should call their healthcare provider or pharmacist if they have any questions.
- Drug Interactions
- REYATAZ may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.
- Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.
- Patients should be informed that REVATIO® (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS®, LEVITRA®, or VIAGRA® (used to treat erectile dysfunction), or ADCIRCA® (used to treat pulmonary arterial hypertension).
- Cardiac Conduction Abnormalities
- Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Patients should consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness.
- Rash
- Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use. These rashes go away within two weeks with no change in treatment. However, there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.
- Hyperbilirubinemia
- Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.
- Nephrolithiasis and Cholelithiasis
- Patients should be informed that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events.
- Fat Redistribution
- Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
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- Content
- Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens. The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.
- Dosage Adjustments in Pregnant Patients
- Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults).
- Renal Impairment
- For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
- Dosage Adjustments in Patients with Hepatic Impairment
- Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.
- Dosage of REYATAZ Capsules in Pediatric Patients
The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).
- Dosage and Administration of REYATAZ Oral Powder in Pediatric Patients
- REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 10 kg and less than 25 kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.
- Instructions for Mixing REYATAZ Oral Powder
- It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.
- Determine the number of packets (4 or 5 packets) that are needed.
- Prior to mixing, tap the packet to settle the powder. Use a clean pair of scissors to cut each packet along the dotted line.
- Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.
- Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be taken at the same time.
- Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.
- Administer ritonavir immediately following REYATAZ powder administration.
- Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation (may leave the mixture at room temperature during this one hour period). Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.
- in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder.
- when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
- when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6).
- Table 6 displays drugs that are contraindicated with REYATAZ.
- Cardiac Conduction Abnormalities
- REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block). ECG monitoring should be considered in these patients.
- Rash
- In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in patients receiving REYATAZ. REYATAZ should be discontinued if severe rash develops.
- Hyperbilirubinemia
- Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established.
- Patients with Phenylketonuria
- Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.
- Hepatotoxicity
- Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment.
- Nephrolithiasis and Cholelithiasis
- Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving REYATAZ therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered.
- Diabetes Mellitus/Hyperglycemia
- New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Fat Redistribution
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Hemophilia
- There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
- Resistance/Cross-Resistance
- Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors.
- The safety profile of REYATAZ in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received REYATAZ 300 mg with ritonavir 100 mg and 1089 patients received REYATAZ 400 mg or higher (without ritonavir).
- The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.
- Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-naive patients receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.
- The safety profile of REYATAZ in treatment-experienced adults is based on 119 HIV-1 infected patients in clinical trials.
- The most common adverse reactions are jaundice/scleral icterus and myalgia.
- Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced patients receiving REYATAZ/ritonavir are presented in Table 9.
- Laboratory Abnormalities in Treatment-Naive Patients
- The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities are presented in Tables 10 and 11, respectively.
- Laboratory Abnormalities in Treatment-Experienced Patients
- The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3–4 laboratory abnormalities are presented in Table 12.
- Lipids, Change from Baseline in Treatment-Naive Patients
- For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 13 and 14, respectively.
- Lipids, Change from Baseline in Treatment-Experienced Patients
- For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.
- The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.
- The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric patients were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of patients. The most common Grade 3–4 laboratory abnormalities occurring in pediatric patients taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.
- The data described below reflect exposure to REYATAZ oral powder in 89 subjects weighing from 10 kg to less than 25 kg, including 65 patients exposed for 48 weeks. These data are from two pooled open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric patients (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 15 months to less than 7.5 years of age. In these studies 53% were female and 47% were male. All patients received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).
- The safety profile of REYATAZ in pediatric patients taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking REYATAZ capsules. The most common Grade 3–4 laboratory abnormalities occurring in pediatric patients weighing 10 kg to less than 25 kg taking REYATAZ oral powder were increased amylase (19%), neutropenia (12%), increased SGPT/ALT (5%), elevation of total bilirubin (≥2.6 times ULN, 12%), increased lipase (5%), and decreased hemoglobin (3%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.
- In study AI424-138, 60 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the REYATAZ/ritonavir-treated patients and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (6/60) of the REYATAZ/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.
- In study AI424-045, 20 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.
- In studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the REYATAZ-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels >5 times ULN developed in 9% of the REYATAZ-treated patients, 5% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients.
- Body as a Whole: edema
- Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation
- Gastrointestinal System: pancreatitis
- Hepatic System: hepatic function abnormalities
- Hepatobiliary Disorders: cholelithiasis, cholecystitis, cholestasis
- Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia
- Musculoskeletal System: arthralgia
- Renal System: nephrolithiasis, interstitial nephritis
- Skin and Appendages: alopecia, maculopapular rash, pruritus, angioedema
- Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.
- Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected.
- The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir.
- Potential for Other Drugs to Affect REYATAZ
- Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect.
- Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with REYATAZ.
- Established and Other Potentially Significant Drug Interactions
- Table 16 provides dosing recommendations as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
- Drugs with No Observed or Predicted Interactions with REYATAZ
- Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8.
- Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, or atenolol.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- Risk Summary
- Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.
- Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.
- Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women. All infants, including neonates exposed to REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.
- Clinical Considerations
- Dosing During Pregnancy and the Postpartum Period:
- REYATAZ should not be administered without ritonavir.
- REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
- For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions:
For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
- For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
- No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
- Human Data
- Clinical Trials: In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.
- Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.
- Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).
- Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
- Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.
- Animal Data
- In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atazanavir in women who are pregnant.
- The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 10 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397. The safety profile in pediatric patients was generally similar to that observed in adults.
### Signs and Symptoms
- Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in an HIV-infected patient (73 times the 400‑mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed.
### Management
- Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Atazanavir in the drug label.
- The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7•H2SO4, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:
- Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C.
- REYATAZ Capsules are available for oral administration in strengths of 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir sulfate, respectively.The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.
- REYATAZ oral powder comes in a packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor.
- Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a placebo-controlled study (AI424-076), the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram.
- Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec.
- Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in HIV-infected adult patients.
- Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Patients
- Absorption
- Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.
- Food Effect
- Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single 400-mg dose of REYATAZ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of REYATAZ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state.
- Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.
- Distribution
- Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in HIV-infected patients dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.
- Metabolism
- Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.
- Elimination
- Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
- Specific Populations
- Renal Impairment
- In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender‑matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
- Hepatic Impairment
- REYATAZ has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment.
- Pediatrics
- The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the powder formulation are summarized in Table 18 by weight ranges that correspond to the recommended doses.
- The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses.
- Pregnancy
- The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules with ritonavir are presented in Table 20.
- Drug Interaction Data
- Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min-1 and Ki value of 0.84 to 1.0 µM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 µM) and CYP2C8 (Ki=2.1 µM).
- Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.
- Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22.
- Mechanism of Action
- Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.
- Antiviral Activity in Cell Culture
- Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.
- Resistance
- In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.
- Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted REYATAZ vs. Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs. REYATAZ 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.
- Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.
- Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.
- Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.
- Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451(PRINCE II): No treatment-emergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other PIs arose in the viruses from one subject each (L19I/R, M36M/I, H69K/R, and I72I/V). None of these viruses acquired phenotypic resistance to ATV, ATV/RTV, or any NNRTI or NRTI. In AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/I, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold change: 1.74, using a commercial investigational assay with an ATV cutoff of 2.2 fold change). Secondary PI substitutions also arose in the viruses of one subject each, including V11V/I, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61/E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from three subjects developed M184V in the reverse transcriptase, and all three exhibited phenotypic resistance to emtricitabine and lamivudine.
- Cross-Resistance
- Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.
- Baseline Genotype/Phenotype and Virologic Outcome Analyses
- Genotypic and/or phenotypic analysis of baseline virus may aid in determining ATV susceptibility before initiation of ATV/RTV therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV twice daily in Study AI424-045 is shown in Table 24.
- Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced patients. In the ATV/RTV group, patients had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to patients with 1–2 PI substitutions, including one of these substitutions.
- The response rates of antiretroviral-experienced patients in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select patient population with 62% of patients receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.
- Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.
- Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).
- At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.
- Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of REYATAZ/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 was a 96-week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range: 19-72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm3 (range: 2 to 810 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.94 log10 copies/mL (range: 2.60 to 5.88 log10 copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26.
- Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the REYATAZ/ritonavir arm and 273 cells/mm3 for the lopinavir/ritonavir arm.
- Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + zidovudine twice daily. Study AI424-034 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm3 (range: 64 to 1424 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.8 log10 copies/mL (range: 2.2 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27.
- Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm3 for the REYATAZ arm and 160 cells/mm3 for the efavirenz arm.
- Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients. Patients had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm3 (range: 4 to 1003 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.7 log10 copies/mL (range: 1.8 to 5.9 log10 copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28.
- Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm3 for the REYATAZ 400-mg arm and 211 cells/mm3 for the nelfinavir arm.
- Adult Patients with Prior Antiretroviral Therapy
- Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 was a randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm3 (range: 14 to 1543 cells/mm3) and the mean baseline plasma HIV-1 RNA level was 4.4 log10 copies/mL (range: 2.6 to 5.88 log10 copies/mL).
- Treatment outcomes through Week 48 for the REYATAZ/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of quantification.
- No patients in the REYATAZ/ritonavir treatment arm and three patients in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.
- In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was −1.55 log10 copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm3. Through 48 weeks of treatment, the proportion of patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy.
- Study AI424-045 also compared changes from baseline in lipid values.
- Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log10 copies/mL in the REYATAZ treatment arm and −2.02 log10 copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.
- Pediatric Patients
- Pediatric Trials with REYATAZ Capsules
- Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs.
- One-hundred five (105) patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm3 in antiretroviral-naive patients and 220 cells/mm3 in antiretroviral-experienced patients.
- Pediatric Trials with REYATAZ Oral Powder
- Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.
AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age
- AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
- AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age
- In these studies 134 patients (73 antiretroviral-naive and 61 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.
- For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.
- Sixty-five (65) patients from both studies weighing 10 kg to less than 25 kg treated with REYATAZ oral powder with ritonavir were evaluated. Patients 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution, and patients 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <400 copies/mL at Week 48 were 78% (32/41) and 71% (17/24), respectively in patients who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively in patients who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy was 412 cells/mm3 (10.5%) in antiretroviral-naive patients and 228 cells/mm3 (6%) in antiretroviral-experienced patients who received REYATAZ oral powder with ritonavir.
- REYATAZ® (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.
- Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
- REYATAZ Oral Powder
- REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each.
- Store REYATAZ oral powder below 30°C (86°F). Once the REYATAZ oral powder is mixed with food or beverage, it may be kept at room temperature 20°C to 30°C (68°F-86°F) for up to 1 hour prior to administration. Store REYATAZ oral powder in the original packet and do not open until ready to use.
- REYATAZ is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a healthcare provider when using REYATAZ.
- Patients should be advised to avoid doing things that can spread HIV infection to others.
- Do not share or re-use needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. It is not known if REYATAZ can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV should not breastfeed because HIV can be passed to the baby in breast milk.
- Dosing Instructions
- Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a healthcare provider while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
- REYATAZ oral powder is available for pediatric patients who are 3 months and older weighing 10 kg to less than 25 kg. Caregivers should be advised on how to mix the REYATAZ oral powder with a food or beverage such as milk or water for infants and young children who can take solid foods or drink liquids from a cup. For infants who cannot take solid food or drink from a cup, the powder formulation mixed in liquid infant formula should be given with an oral dosing syringe. Caregivers should carefully follow the Instructions for Use and storage of the powder.
- Caregivers of patients with phenylketonuria should be advised that REYATAZ oral powder contains phenylalanine.
- Patients or caregivers should call their healthcare provider or pharmacist if they have any questions.
- Drug Interactions
- REYATAZ may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.
- Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.
- Patients should be informed that REVATIO® (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS®, LEVITRA®, or VIAGRA® (used to treat erectile dysfunction), or ADCIRCA® (used to treat pulmonary arterial hypertension).
- Cardiac Conduction Abnormalities
- Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Patients should consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness.
- Rash
- Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use. These rashes go away within two weeks with no change in treatment. However, there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.
- Hyperbilirubinemia
- Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.
- Nephrolithiasis and Cholelithiasis
- Patients should be informed that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events.
- Fat Redistribution
- Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
- ↑ "REYATAZ (atazanavir) capsule, gelatin coated [E.R. Squibb & Sons, L.L.C.]"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "http://www.ismp.org". External link in |title= (help) | https://www.wikidoc.org/index.php/ATV | |
60b305a4a75556ae11791c65fe1bd2aff0d25603 | wikidoc | Zidovudine | Zidovudine
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# Black Box Warning
# Overview
Zidovudine is an anti-HIV agent, anti-infective agent that is FDA approved for the treatment of HIV-1, prevention of maternal-fetal HIV-1 transmission. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, malaise, nausea, anorexia and vomiting, fever, cough, digestive disorders, anemia, and neutropenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zidovudine tablets USP, a nucleoside reverse transcriptase inhibitor, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
- Dosing Information
- For the treatment of HIV infection in adults, the recommended dose is 1 mg/kg IV infused over 1 hour 5 to 6 times a day. The patient should be switched to oral therapy as soon as possible.
- 600 mg/day ORALLY in divided doses.
- HIV infection: 1 mg/kg/dose IV 5 to 6 times a day.
- Zidovudine tablets are indicated for the prevention of maternal-fetal HIV-1 transmission. The indication is based on a dosing regimen that included three components:
- antepartum therapy of HIV-1 infected mothers
- intrapartum therapy of HIV-1 infected mothers
- post-partum therapy of HIV-1 exposed neonate
- Points to consider prior to initiating zidovudine tablets in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:
- In most cases, zidovudine tablets for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
- Prevention of HIV-1 transmission in women who have received zidovudine tablets for a prolonged period before pregnancy has not been evaluated.
- Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with zidovudine tablets during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.
- Dosing Information
- Maternal Dosing:
- In HIV-infected women with HIV RNA levels greater than 400 copies/mL (or unknown HIV RNA) near delivery, regardless of antiretroviral therapy, the recommended regimen during labor and delivery (intrapartum) is zidovudine 2 mg/kg IV infused over 1 hour, followed by a continuous infusion of 1 mg/kg/hr until the umbilical cord is clamped. If a cesarean delivery is planned, the zidovudine IV infusion should begin 3 hours prior to scheduled delivery. If IV administration is not feasible, oral administration of zidovudine may be considered. Combination antiretroviral therapy should be initiated and/or continued throughout the antepartum and intrapartum period in the mother; however, oral zidovudine, taken as part of an antiretroviral regimen, should be discontinued during intrapartum IV zidovudine administration. Dose zidovudine per total body weight.
- During pregnancy (greater than 14 week of pregnancy), 100 mg ORALLY 5 times daily until the start of labor.
- HIV infection, Perinatal transmission; Prophylaxis: intrapartum dosing, 2 mg/kg (total body weight) IV over 1 hour, followed by 1 mg/kg (total body weight)/hr IV infusion during labor and until umbilical cord clamping.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Adult, Category C
- Dosing Information
- Important Note:
- Two combination products, Combivir(R) (lamivudine 150 mg and zidovudine 300 mg) and Trizivir(TM) (abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg), are available. Retrovir(R) (zidovudine) should not be used in combination with Combivir(R) or Trizivir(R). See combination drug monographs for specific information on the combination products.
- Dosage Equivalent:
- Oral zidovudine 100 mg every 4 hours is approximately equal to 1 mg/kg IV every 4 hours.
### Non–Guideline-Supported Use
- Dosing Information
- For the treatment of human T-cell lymphotropic virus-I-associated adult T-cell leukemia/lymphoma, combination therapy with zidovudine 50 to 200 mg/dose orally 5 times daily plus interferon alfa-2b (Intron® A) 2.5 to 5 million units subQ once daily was studied in a small multicenter, single-arm, open-label trial. Doses were increased to zidovudine 200 mg/dose and interferon alfa 10 million units subQ once daily within 10 days if treatment was tolerated. Treatment was continued for 12 months in patients who achieved a complete or partial response. Granulocyte colony-stimulating factor use was permitted if severe neutropenia occurred (neutrophil count less than 500 cells/mm(3)).
- For the treatment of human T-cell lymphotropic virus-I-associated acute or lymphomatous adult T-cell leukemia/lymphoma, combination therapy with zidovudine 200 mg orally every 4 hours while awake for a total of 5 doses (1000 mg)/day plus interferon alfa-2b (Intron® A) 5 million units subQ once daily was studied in a small multicenter, single-arm, open-label trial. The interferon alfa dosage was increased to 10 million units subQ once daily after 1 week if treatment was tolerated. Treatment was continued for 4 weeks past a complete response or for up to 1 year.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Postpartum, the recommended IV dose in full-term neonates/infants younger than 6 weeks is 3 mg/kg every 12 hours. The recommended dose in preterm neonates (gestational age 30 weeks or greater to less than 35 weeks) 1.5 mg/kg IV every 12 hours advancing to 2.3 mg/kg IV every 12 hours at 15 days of age. If less than 30 weeks gestation at birth, the recommended dose is 1.5 mg/kg IV every 12 hours advancing to 2.3 mg/kg IV every 12 hours after 4 weeks of age.
- Manufacturer Dosing:
- The recommended dose in HIV-infected infants and children 4 weeks or older, weighing 4 kg or greater, is listed in the table below. Zidovudine syrup should be used to provide accurate dosage when whole tablets or capsules are not appropriate.
- Alternatively, using body surface area, the recommended dose in HIV-infected infants and children 4 weeks or older is 240 mg/m(2) orally twice daily or 160 mg/m(2) orally 3 times daily daily, not to exceed adult dosage of 600 mg/day.
- Guideline Dosing:
- The Department of Health and Human Services HIV treatment guidelines recommended doses in HIV-infected infants and children 6 weeks or older are as follows: for infants and children weighing 4 kg to less than 9 kg, the dose is 12 mg/kg twice daily; for children weighing 9 kg to less than 30 kg, the dose is 9 mg/kg twice daily; and for children weighing 30 kg or more, the dose is 300 mg twice daily. Alternatively, body surface area dosing of 180 to 240 mg/m(2) orally twice daily, or 160 mg/m(2) orally every 8 hours, may be used.
- The recommended oral doses for treating HIV-infected infants younger than 6 weeks are full-term neonates (gestational age 35 weeks or greater) 4 mg/kg every 12 hours; premature neonates (30 weeks or greater to less than 35 weeks gestational age) 2 mg/kg every 12 hours advancing to 3 mg/kg every 12 hours at 15 days of age; and for less than 30 weeks gestational age, the recommended dose is 2 mg/kg every 12 hours advancing to 3 mg/kg every 12 hours after 4 weeks of age.
### HIV infection, Perinatal transmission; Prophylaxis
- Dosing Information
- Neonatal Manufacturer Dosing:
- In neonates unable to receive oral dosing, zidovudine 1.5 mg/kg IV, infused over 30 minutes, every 6 hours (6 mg/kg/day) may be used.
- Neonatal Guideline Dosing:
- In neonates unable to receive oral dosing, IV zidovudine may be considered. For full-term neonates (gestational age of 35 weeks or greater at birth) the recommended IV dose of zidovudine is 3 mg/kg (infused over 30 minutes) every 12 hours. Preterm neonatal dosing is 1.5 mg/kg IV every 12 hours for infants less than 35 weeks' gestational age. Advance the dose to 2.3 mg/kg IV every 12 hours at 15 days of age for infants 30 weeks to less than 35 weeks gestation at birth; and advance dose at 4 weeks of age for infants less than 30 weeks gestation at birth. Zidovudine therapy should be initiated within 6 to 12 hours of birth and continued through 6 weeks of age. For infants born to HIV-infected women who have NOT received antiretroviral therapy prior to labor, 3 doses of nevirapine should be given in addition to zidovudine during the first week of life (each dose is 8 mg orally for infants 1.5 to 2 kg birthweight and 12 mg orally for infants weighing greater than 2 kg); give first dose at birth within 48 hours of birth, second dose 48 hours after first dose, and third dose 96 hours after second dose.
- Neonatal Manufacturer Dosing:
- The neonate should receive zidovudine 2 mg/kg orally every 6 hours (8 mg/kg/day) for 6 weeks; initiate within 12 hours of birth. In neonates unable to receive oral dosing, zidovudine 1.5 mg/kg IV, infused over 30 minutes, every 6 hours (6 mg/kg/day) may be used.
- Neonatal Guideline Dosing:
- The full-term neonate (gestational age of 35 weeks or greater) should receive zidovudine 4 mg/kg orally twice daily for 6 weeks; initiate within 6 to 12 hours of birth. Preterm neonatal dosing for infants with a gestational age less than 35 weeks is 2 mg/kg orally every 12 hours. Advance the dose to 3 mg/kg every 12 hours at 15 days of age for infants 30 weeks to less than 35 weeks gestation at birth. Advance the dose to 3 mg/kg every 12 hours at 4 weeks of age for infants less than 30 weeks gestation at birth. Zidovudine therapy should be initiated within 6 to 12 hours of birth and continued through 6 weeks of age. In infants unable to receive oral dosing, appropriate doses of IV zidovudine may be used. For infants born to HIV-infected women who have NOT received antiretroviral therapy prior to labor, 3 doses of nevirapine should be given in addition to zidovudine during the first week of life (each dose is 8 mg orally for infants 1.5 to 2 kg birthweight and 12 mg orally for infants weighing greater than 2 kg); give first dose within 48 hours of birth, second dose 48 hours after first dose, and third dose 96 hours after second dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Class of Recommendation: Pediatric, Class IIa
- Strength of Evidence: Pediatric, Category C
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Zidovudine in pediatric patients.
# Contraindications
- Zidovudine tablets are contraindicated in patients who have had potentially life threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson Syndrome) to any of the components of the formulations.
# Warnings
Hematologic Toxicity/Bone Marrow Suppression
- Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1,000 cells/mm3 or hemoglobin < 9.5 g/dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of zidovudine, and/or blood transfusions, has occurred during treatment with zidovudine alone or in combination with other antiretrovirals.
- Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with zidovudine. For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed.
Myopathy
- Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering zidovudine to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with zidovudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Use with Interferon- and Ribavirin-based Regimens in HIV-1/HCV Co-infected Patients
- In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients, exacerbation of anemia due to ribavirin has been reported when zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not advised. Consideration should be given to replacing zidovudine in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
- Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia and anemia.
- Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6) (see the complete prescribing information for interferon and ribavirin).
Use with Other Zidovudine-containing Products
- Zidovudine tablets should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR®- Tablets or TRIZIVIR®- ], lamivudine, and zidovudine] Tablets).
Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including zidovudine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable and can occur many months after initiation of treatment.
Fat Redistribution
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance”, have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Hematologic toxicity, including neutropenia and anemia.
- Symptomatic myopathy.
- Lactic acidosis and severe hepatomegaly with steatosis.
- Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults
- The frequency and severity of adverse reactions associated with the use of zidovudine are greater in patients with more advanced infection at the time of initiation of therapy.
- Table 3 summarizes events reported at a statistically significant greater incidence for patients receiving zidovudine in a monotherapy study.
- In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of ≥ 5% in any treatment arm in clinical studies (NUCA3001, NUCA3002, NUCB3001 and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia and neuropathy. Additionally, in these studies hyperbilirubinemia was reported at an incidence of ≤ 0.8%.
- Selected laboratory abnormalities observed during a clinical study of monotherapy with zidovudine are shown in Table 4.
- ULN = Upper limit of normal.
Pediatrics
- The clinical adverse reactions reported among adult recipients of zidovudine may also occur in pediatric patients.
Study ACTG 300
- Selected clinical adverse reactions and physical findings with a ≥ 5% frequency during therapy with EPIVIR®- (lamivudine) Oral Suspension 4 mg/kg twice daily plus zidovudine 160 mg/m2 three times daily compared with didanosine in therapy-naive (≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 5.
- Selected laboratory abnormalities experienced by therapy-naive (≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 6.
- Macrocytosis was reported in the majority of pediatric patients receiving zidovudine 180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an incidence of < 6% in these studies were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability and weight loss.
Use for the Prevention of Maternal-Fetal Transmission of HIV-1
- In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission, zidovudine syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia (hemoglobin < 9 g/dL) and neutropenia (< 1,000 cells/mm3). Anemia occurred in 22% of the neonates who received zidovudine and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1 g/dL for neonates receiving zidovudine compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with zidovudine. Neutropenia in neonates was reported with similar frequency in the group that received zidovudine (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to zidovudine are unknown.
## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-marketing use of zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zidovudine.
- Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat.
- Cardiovascular: Cardiomyopathy, syncope.
- Endocrine: Gynecomastia.
- Eye: Macular edema.
- Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
- General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
- Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
- Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.
- Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.
- Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.
- Respiratory: Dyspnea, rhinitis, sinusitis.
- Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweat, urticaria.
- Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
- Urogenital: Urinary frequency, urinary hesitancy.
# Drug Interactions
Antiretroviral Agents
Stavudine
- Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.
Nucleoside Analogues Affecting DNA Replication
- Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided.
Doxorubicin
- Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
- Coadministration of ganciclovir, interferon alfa, ribavirin and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects
- In humans, treatment with zidovudine during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.
- A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1-transmission. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
- Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose.
Antiretroviral Pregnancy Registry
- To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zidovudine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Zidovudine during labor and delivery.
### Nursing Mothers
- Zidovudine is excreted in human milk. The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breast-feed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving zidovudine.
### Pediatric Use
- Zidovudine has been studied in HIV-1-infected pediatric patients ≥ 6 weeks of age who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. Zidovudine has also been studied in neonates perinatally exposed to HIV-1.
### Geriatic Use
- Clinical studies of zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
### Gender
- There is no FDA guidance on the use of Zidovudine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Zidovudine with respect to specific racial populations.
### Renal Impairment
- In patients with severely impaired renal function (CrCl < 15 mL/min), dosage reduction is recommended.
### Hepatic Impairment
- Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function, which may increase the risk of hematologic toxicity.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Zidovudine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Zidovudine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Treatment of HIV-1 Infection
Adults
- The recommended oral dose of zidovudine tablets is 600 mg/day in divided doses in combination with other antiretroviral agents.
Pediatric Patients (Aged 4 Weeks to <18 Years)
- Healthcare professionals should pay special attention to accurate calculation of the dose of zidovudine tablets, transcription of the medication order, dispensing information and dosing instructions to minimize risk for medication dosing errors.
- Prescribers should calculate the appropriate dose of zidovudine tablets for each child based on body weight (kg) and should not exceed the recommended adult dose.
- Before prescribing zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a zidovudine tablet, the zidovudine syrup formulation should be prescribed.
- The recommended dosage in pediatric patients 4 weeks of age and older and weighing ≥ 4 kg is provided in Table 1. Zidovudine syrup should be used to provide accurate dosage when whole tablets are not appropriate.
- Alternatively, dosing for zidovudine tablets can be based on body surface area (BSA) for each child. The recommended oral dose of zidovudine tablets is 480 mg/m2/day in divided doses (240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.
Prevention of Maternal-Fetal HIV-1 Transmission
- The recommended dosage regimen for administration to pregnant women (> 14 weeks of pregnancy) and their neonates is:
Maternal Dosing
- 100 mg orally 5 times per day until the start of labor. During labor and delivery, intravenous zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal Dosing
- Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered zidovudine intravenously. See Table 2.
Patients with Severe Anemia and/or Neutropenia
- Significant anemia (hemoglobin 25% of baseline) and/or significant neutropenia (granulocyte count 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed. In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level and patient tolerance.
Patients with Renal Impairment
End-Stage Renal Disease
- In patients maintained on hemodialysis or peritoneal dialysis, the recommended dosage is 100 mg every 6 to 8 hours.
Patients with Hepatic Impairment
- There are insufficient data to recommend dose adjustment of zidovudine tablets in patients with mild to moderate impaired hepatic function or liver cirrhosis.
DOSAGE FORMS AND STRENGTHS
Zidovudine Tablets
- The 300 mg tablets are white to off-white film-coated, round, unscored tablets debossed with M 106 on one side of the tablet and blank on the other side.
### Monitoring
- There is limited information regarding Monitoring of Zidovudine in the drug label.
- Description
# IV Compatibility
- There is limited information regarding IV Compatibility of Zidovudine in the drug label.
# Overdosage
- Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting and occasional reports of hematological disturbances. All patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3’-azido-3’-deoxy-5’-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
# Pharmacology
## Mechanism of Action
- Zidovudine is an antiviral agent.
## Structure
- Zidovudine (formerly called azidothymidine ), is a pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3’-Azido-3’-deoxythymidine; it has the following structural formula:
- Zidovudine, USP is a white to yellowish powder with a molecular weight of 267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
- Zidovudine tablets, USP are for oral administration. Each film-coated tablet contains 300 mg of zidovudine, USP and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Zidovudine in the drug label.
## Pharmacokinetics
Absorption and Bioavailability
- In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as zidovudine tablets or syrup compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult patients are summarized in Table 7.
Distribution
- The apparent volume of distribution of zidovudine, following oral administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, < 38% (Table 7).
Metabolism and Elimination
- Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second metabolite, 3’-amino-3’-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
Effect of Food on Absorption
- Zidovudine may be administered with or without food. The zidovudine AUC was similar when a single dose of zidovudine was administered with food.
Special Populations
Renal Impairment
- Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14) following a single 200 mg oral dose (Table 8). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥ 15 mL/min.
Hemodialysis and Peritoneal Dialysis
- The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg five times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis.
Hepatic Impairment
- Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma concentrations would be increased following administration of the recommended adult doses to patients with hepatic impairment.
Pediatric Patients
- Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric patients (Table 9).
Patients Aged 3 Months to 12 Years
- Overall, zidovudine pharmacokinetics in pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life and oral clearance were comparable to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.
Patients Aged Less Than 3 Months
- Zidovudine pharmacokinetics have been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in eight neonates who were exposed to zidovudine in utero. The half-life was 13 ± 5.8 hours. In neonates ≤ 14 days old, bioavailability was greater, total body clearance was slower and half-life was longer than in pediatric patients > 14 days old. For dose recommendations for neonates.
Pregnancy
- Zidovudine pharmacokinetics have been studied in a Phase I study of eight women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.
- Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter zidovudine pharmacokinetics.
Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum.
Geriatric Patients
- Zidovudine pharmacokinetics have not been studied in patients over 65 years of age.
Gender
- A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine AUC when a single dose of zidovudine was administered as the 300 mg zidovudine tablet.
Drug Interactions
Phenytoin
- Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine, while in one case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single 300 mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Ribavirin
- In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multidrug regimen to HIV-1/HCV co-infected patients.
Microbiology
Mechanism of Action
- Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5’-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity
- The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg/mL) and 0.1 to 9 µM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049 to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
Resistance
- Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of substitutions conferring resistance to zidovudine.
Cross-resistance
- In a study of 167 HIV-1-infected patients, isolates (n = 2) with multidrug resistance to didanosine, lamivudine, stavudine, zalcitabine and zidovudine were recovered from patients treated for ≥ 1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multidrug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77 and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir and zalcitabine.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Zidovudine was administered orally at three dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60 and 120 mg/kg/day in mice and 80, 220 and 600 mg/kg/day in rats. The doses in mice were reduced to 20, 30 and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on day 279.
- In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma and one squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
- In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
- At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
- It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
- Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.
- Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, had no effect on fertility judged by conception rates.
- Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine administered in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1000 mg/kg nonpregnant body weight or ~ 450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
Reproductive and Developmental Toxicology Studies
- Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3000 mg/kg/day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
# Clinical Studies
- Therapy with zidovudine has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.
Adults
Combination Therapy
- Zidovudine in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
- The clinical efficacy of a combination regimen that includes zidovudine was demonstrated in study ACTG 320. This study was a multi-center, randomized, double-blind, placebo-controlled trial that compared zidovudine 600 mg/day plus EPIVIR®- 300 mg/day to zidovudine plus EPIVIR®- plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm (6.1% vs. 10.9%, respectively).
Monotherapy
- In controlled studies of treatment-naive patients conducted between 1986 and 1989, monotherapy with zidovudine, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts between 200 and 500 cells/mm3 (ACTG 016 and ACTG 019). A survival benefit for monotherapy with zidovudine was not demonstrated in the latter two studies. Subsequent studies showed that the clinical benefit of monotherapy with zidovudine was time limited.
Pediatric Patients
- ACTG 300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR®- plus zidovudine to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these two treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration that patients remained on study was approximately 10 months. Results are summarized in Table 11.
Prevention of Maternal-Fetal HIV-1 Transmission
- The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for 6 weeks. The study showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.
# How Supplied
- Zidovudine Tablets, USP are available containing 300 mg of zidovudine, USP.
- The 300 mg tablets are white to off-white film-coated, round, unscored tablets debossed with M 106 on one side of the tablet and blank on the other side. They are available as follows:
- NDC 0378-6106-91
- bottles of 60 tablets
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from moisture.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advice for the Patient
Neutropenia and Anemia
- Patients should be informed that the major toxicities of zidovudine are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. Patients should be informed that if toxicity develops, they may require transfusions or drug discontinuation. Patients should be informed of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease.
Myopathy
- Patients should be informed that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.
Lactic Acidosis/Hepatomegaly
- Patients should be informed that some HIV medicines, including zidovudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
HIV-1/HCV Co-infection
- Patients with HIV-1/HCV co-infection should be informed that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin .
Use with Other Zidovudine-containing Products
- Zidovudine tablets should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR®- Tablets or TRIZIVIR®- Tablets).
Redistribution/Accumulation of Body Fat
- Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Common Adverse Reactions
- Patients should be informed that the most commonly reported adverse reactions in adult patients being treated with zidovudine were headache, malaise, nausea, anorexia and vomiting. The most commonly reported adverse reactions in pediatric patients receiving zidovudine were fever, cough and digestive disorders. Patients also should be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with zidovudine.
Drug Interactions
- Patients should be cautioned about the use of other medications, including ganciclovir, interferon alfa and ribavirin, which may exacerbate the toxicity of zidovudine.
Pregnancy
- Pregnant women considering the use of zidovudine during pregnancy for prevention of HIV-1 transmission to their infants should be informed that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to zidovudine are unknown, including the possible risk of cancer.
- HIV-1-infected pregnant women should be informed not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.
Information About HIV-1 Infection
- Ziduvine is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using zidovudine tablets.
- Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions or blood.
- Do not breast-feed. Zidovudine is excreted in human breast milk. Mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in the breast milk.
- Patients should be informed to take all HIV medications exactly as prescribed.
# Precautions with Alcohol
- Alcohol-Zidovudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Retrovir
# Look-Alike Drug Names
There is limited information regarding Zidovudine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Zidovudine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]
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# Black Box Warning
# Overview
Zidovudine is an anti-HIV agent, anti-infective agent that is FDA approved for the treatment of HIV-1, prevention of maternal-fetal HIV-1 transmission. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, malaise, nausea, anorexia and vomiting, fever, cough, digestive disorders, anemia, and neutropenia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Zidovudine tablets USP, a nucleoside reverse transcriptase inhibitor, are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
- Dosing Information
- For the treatment of HIV infection in adults, the recommended dose is 1 mg/kg IV infused over 1 hour 5 to 6 times a day. The patient should be switched to oral therapy as soon as possible.
- 600 mg/day ORALLY in divided doses.
- HIV infection: 1 mg/kg/dose IV 5 to 6 times a day.
- Zidovudine tablets are indicated for the prevention of maternal-fetal HIV-1 transmission. The indication is based on a dosing regimen that included three components:
- antepartum therapy of HIV-1 infected mothers
- intrapartum therapy of HIV-1 infected mothers
- post-partum therapy of HIV-1 exposed neonate
- Points to consider prior to initiating zidovudine tablets in pregnant women for the prevention of maternal-fetal HIV-1 transmission include:
- In most cases, zidovudine tablets for prevention of maternal-fetal HIV-1 transmission should be given in combination with other antiretroviral drugs.
- Prevention of HIV-1 transmission in women who have received zidovudine tablets for a prolonged period before pregnancy has not been evaluated.
- Because the fetus is most susceptible to the potential teratogenic effects of drugs during the first 10 weeks of gestation and the risks of therapy with zidovudine tablets during that period are not fully known, women in the first trimester of pregnancy who do not require immediate initiation of antiretroviral therapy for their own health may consider delaying use; this indication is based on use after 14 weeks gestation.
- Dosing Information
- Maternal Dosing:
- In HIV-infected women with HIV RNA levels greater than 400 copies/mL (or unknown HIV RNA) near delivery, regardless of antiretroviral therapy, the recommended regimen during labor and delivery (intrapartum) is zidovudine 2 mg/kg IV infused over 1 hour, followed by a continuous infusion of 1 mg/kg/hr until the umbilical cord is clamped. If a cesarean delivery is planned, the zidovudine IV infusion should begin 3 hours prior to scheduled delivery. If IV administration is not feasible, oral administration of zidovudine may be considered. Combination antiretroviral therapy should be initiated and/or continued throughout the antepartum and intrapartum period in the mother; however, oral zidovudine, taken as part of an antiretroviral regimen, should be discontinued during intrapartum IV zidovudine administration. Dose zidovudine per total body weight.
- During pregnancy (greater than 14 week of pregnancy), 100 mg ORALLY 5 times daily until the start of labor.
- HIV infection, Perinatal transmission; Prophylaxis: intrapartum dosing, 2 mg/kg (total body weight) IV over 1 hour, followed by 1 mg/kg (total body weight)/hr IV infusion during labor and until umbilical cord clamping.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Class of Recommendation: Adult, Class IIa
- Strength of Evidence: Adult, Category C
- Dosing Information
- Important Note:
- Two combination products, Combivir(R) (lamivudine 150 mg and zidovudine 300 mg) and Trizivir(TM) (abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg), are available. Retrovir(R) (zidovudine) should not be used in combination with Combivir(R) or Trizivir(R). See combination drug monographs for specific information on the combination products.
- Dosage Equivalent:
- Oral zidovudine 100 mg every 4 hours is approximately equal to 1 mg/kg IV every 4 hours.
### Non–Guideline-Supported Use
- Dosing Information
- For the treatment of human T-cell lymphotropic virus-I-associated adult T-cell leukemia/lymphoma, combination therapy with zidovudine 50 to 200 mg/dose orally 5 times daily plus interferon alfa-2b (Intron® A) 2.5 to 5 million units subQ once daily was studied in a small multicenter, single-arm, open-label trial. Doses were increased to zidovudine 200 mg/dose and interferon alfa 10 million units subQ once daily within 10 days if treatment was tolerated. Treatment was continued for 12 months in patients who achieved a complete or partial response. Granulocyte colony-stimulating factor use was permitted if severe neutropenia occurred (neutrophil count less than 500 cells/mm(3)).
- For the treatment of human T-cell lymphotropic virus-I-associated acute or lymphomatous adult T-cell leukemia/lymphoma, combination therapy with zidovudine 200 mg orally every 4 hours while awake for a total of 5 doses (1000 mg)/day plus interferon alfa-2b (Intron® A) 5 million units subQ once daily was studied in a small multicenter, single-arm, open-label trial. The interferon alfa dosage was increased to 10 million units subQ once daily after 1 week if treatment was tolerated. Treatment was continued for 4 weeks past a complete response or for up to 1 year.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Postpartum, the recommended IV dose in full-term neonates/infants younger than 6 weeks is 3 mg/kg every 12 hours. The recommended dose in preterm neonates (gestational age 30 weeks or greater to less than 35 weeks) 1.5 mg/kg IV every 12 hours advancing to 2.3 mg/kg IV every 12 hours at 15 days of age. If less than 30 weeks gestation at birth, the recommended dose is 1.5 mg/kg IV every 12 hours advancing to 2.3 mg/kg IV every 12 hours after 4 weeks of age.
- Manufacturer Dosing:
- The recommended dose in HIV-infected infants and children 4 weeks or older, weighing 4 kg or greater, is listed in the table below. Zidovudine syrup should be used to provide accurate dosage when whole tablets or capsules are not appropriate.
- Alternatively, using body surface area, the recommended dose in HIV-infected infants and children 4 weeks or older is 240 mg/m(2) orally twice daily or 160 mg/m(2) orally 3 times daily daily, not to exceed adult dosage of 600 mg/day.
- Guideline Dosing:
- The Department of Health and Human Services HIV treatment guidelines recommended doses in HIV-infected infants and children 6 weeks or older are as follows: for infants and children weighing 4 kg to less than 9 kg, the dose is 12 mg/kg twice daily; for children weighing 9 kg to less than 30 kg, the dose is 9 mg/kg twice daily; and for children weighing 30 kg or more, the dose is 300 mg twice daily. Alternatively, body surface area dosing of 180 to 240 mg/m(2) orally twice daily, or 160 mg/m(2) orally every 8 hours, may be used.
- The recommended oral doses for treating HIV-infected infants younger than 6 weeks are full-term neonates (gestational age 35 weeks or greater) 4 mg/kg every 12 hours; premature neonates (30 weeks or greater to less than 35 weeks gestational age) 2 mg/kg every 12 hours advancing to 3 mg/kg every 12 hours at 15 days of age; and for less than 30 weeks gestational age, the recommended dose is 2 mg/kg every 12 hours advancing to 3 mg/kg every 12 hours after 4 weeks of age.
### HIV infection, Perinatal transmission; Prophylaxis
- Dosing Information
- Neonatal Manufacturer Dosing:
- In neonates unable to receive oral dosing, zidovudine 1.5 mg/kg IV, infused over 30 minutes, every 6 hours (6 mg/kg/day) may be used.
- Neonatal Guideline Dosing:
- In neonates unable to receive oral dosing, IV zidovudine may be considered. For full-term neonates (gestational age of 35 weeks or greater at birth) the recommended IV dose of zidovudine is 3 mg/kg (infused over 30 minutes) every 12 hours. Preterm neonatal dosing is 1.5 mg/kg IV every 12 hours for infants less than 35 weeks' gestational age. Advance the dose to 2.3 mg/kg IV every 12 hours at 15 days of age for infants 30 weeks to less than 35 weeks gestation at birth; and advance dose at 4 weeks of age for infants less than 30 weeks gestation at birth. Zidovudine therapy should be initiated within 6 to 12 hours of birth and continued through 6 weeks of age. For infants born to HIV-infected women who have NOT received antiretroviral therapy prior to labor, 3 doses of nevirapine should be given in addition to zidovudine during the first week of life (each dose is 8 mg orally for infants 1.5 to 2 kg birthweight and 12 mg orally for infants weighing greater than 2 kg); give first dose at birth within 48 hours of birth, second dose 48 hours after first dose, and third dose 96 hours after second dose.
- Neonatal Manufacturer Dosing:
- The neonate should receive zidovudine 2 mg/kg orally every 6 hours (8 mg/kg/day) for 6 weeks; initiate within 12 hours of birth. In neonates unable to receive oral dosing, zidovudine 1.5 mg/kg IV, infused over 30 minutes, every 6 hours (6 mg/kg/day) may be used.
- Neonatal Guideline Dosing:
- The full-term neonate (gestational age of 35 weeks or greater) should receive zidovudine 4 mg/kg orally twice daily for 6 weeks; initiate within 6 to 12 hours of birth. Preterm neonatal dosing for infants with a gestational age less than 35 weeks is 2 mg/kg orally every 12 hours. Advance the dose to 3 mg/kg every 12 hours at 15 days of age for infants 30 weeks to less than 35 weeks gestation at birth. Advance the dose to 3 mg/kg every 12 hours at 4 weeks of age for infants less than 30 weeks gestation at birth. Zidovudine therapy should be initiated within 6 to 12 hours of birth and continued through 6 weeks of age. In infants unable to receive oral dosing, appropriate doses of IV zidovudine may be used. For infants born to HIV-infected women who have NOT received antiretroviral therapy prior to labor, 3 doses of nevirapine should be given in addition to zidovudine during the first week of life (each dose is 8 mg orally for infants 1.5 to 2 kg birthweight and 12 mg orally for infants weighing greater than 2 kg); give first dose within 48 hours of birth, second dose 48 hours after first dose, and third dose 96 hours after second dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Class of Recommendation: Pediatric, Class IIa
- Strength of Evidence: Pediatric, Category C
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Zidovudine in pediatric patients.
# Contraindications
- Zidovudine tablets are contraindicated in patients who have had potentially life threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson Syndrome) to any of the components of the formulations.
# Warnings
Hematologic Toxicity/Bone Marrow Suppression
- Zidovudine should be used with caution in patients who have bone marrow compromise evidenced by granulocyte count < 1,000 cells/mm3 or hemoglobin < 9.5 g/dL. Hematologic toxicities appear to be related to pretreatment bone marrow reserve and to dose and duration of therapy. In patients with advanced symptomatic HIV-1 disease, anemia and neutropenia were the most significant adverse events observed. In patients who experience hematologic toxicity, a reduction in hemoglobin may occur as early as 2 to 4 weeks, and neutropenia usually occurs after 6 to 8 weeks. There have been reports of pancytopenia associated with the use of zidovudine, which was reversible in most instances after discontinuance of the drug. However, significant anemia, in many cases requiring dose adjustment, discontinuation of zidovudine, and/or blood transfusions, has occurred during treatment with zidovudine alone or in combination with other antiretrovirals.
- Frequent blood counts are strongly recommended to detect severe anemia or neutropenia in patients with poor bone marrow reserve, particularly in patients with advanced HIV-1 disease who are treated with zidovudine. For HIV-1-infected individuals and patients with asymptomatic or early HIV-1 disease, periodic blood counts are recommended. If anemia or neutropenia develops, dosage interruption may be needed.
Myopathy
- Myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.
Lactic Acidosis/Severe Hepatomegaly with Steatosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including zidovudine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged exposure to antiretroviral nucleoside analogues may be risk factors. Particular caution should be exercised when administering zidovudine to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with zidovudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Use with Interferon- and Ribavirin-based Regimens in HIV-1/HCV Co-infected Patients
- In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as zidovudine. Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with zidovudine in HIV-1/HCV co-infected patients, exacerbation of anemia due to ribavirin has been reported when zidovudine is part of the HIV regimen. Coadministration of ribavirin and zidovudine is not advised. Consideration should be given to replacing zidovudine in established combination HIV-1/HCV therapy, especially in patients with a known history of zidovudine-induced anemia.
- Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Patients receiving interferon alfa with or without ribavirin and zidovudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation, neutropenia and anemia.
- Discontinuation of zidovudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh > 6) (see the complete prescribing information for interferon and ribavirin).
Use with Other Zidovudine-containing Products
- Zidovudine tablets should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR®* [lamivudine and zidovudine] Tablets or TRIZIVIR®* [[[abacavir sulfate]], lamivudine, and zidovudine] Tablets).
Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including zidovudine. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves’ disease, polymyositis and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable and can occur many months after initiation of treatment.
Fat Redistribution
- Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and “cushingoid appearance”, have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Hematologic toxicity, including neutropenia and anemia.
- Symptomatic myopathy.
- Lactic acidosis and severe hepatomegaly with steatosis.
- Hepatic decompensation in patients co-infected with HIV-1 and hepatitis C.
Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adults
- The frequency and severity of adverse reactions associated with the use of zidovudine are greater in patients with more advanced infection at the time of initiation of therapy.
- Table 3 summarizes events reported at a statistically significant greater incidence for patients receiving zidovudine in a monotherapy study.
- In addition to the adverse reactions listed in Table 3, adverse reactions observed at an incidence of ≥ 5% in any treatment arm in clinical studies (NUCA3001, NUCA3002, NUCB3001 and NUCB3002) were abdominal cramps, abdominal pain, arthralgia, chills, dyspepsia, fatigue, insomnia, musculoskeletal pain, myalgia and neuropathy. Additionally, in these studies hyperbilirubinemia was reported at an incidence of ≤ 0.8%.
- Selected laboratory abnormalities observed during a clinical study of monotherapy with zidovudine are shown in Table 4.
- ULN = Upper limit of normal.
Pediatrics
- The clinical adverse reactions reported among adult recipients of zidovudine may also occur in pediatric patients.
Study ACTG 300
- Selected clinical adverse reactions and physical findings with a ≥ 5% frequency during therapy with EPIVIR®* (lamivudine) Oral Suspension 4 mg/kg twice daily plus zidovudine 160 mg/m2 three times daily compared with didanosine in therapy-naive (≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 5.
- Selected laboratory abnormalities experienced by therapy-naive (≤ 56 days of antiretroviral therapy) pediatric patients are listed in Table 6.
- Macrocytosis was reported in the majority of pediatric patients receiving zidovudine 180 mg/m2 every 6 hours in open-label studies. Additionally, adverse reactions reported at an incidence of < 6% in these studies were congestive heart failure, decreased reflexes, ECG abnormality, edema, hematuria, left ventricular dilation, nervousness/irritability and weight loss.
Use for the Prevention of Maternal-Fetal Transmission of HIV-1
- In a randomized, double-blind, placebo-controlled trial in HIV-1-infected women and their neonates conducted to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission, zidovudine syrup at 2 mg/kg was administered every 6 hours for 6 weeks to neonates beginning within 12 hours following birth. The most commonly reported adverse reactions were anemia (hemoglobin < 9 g/dL) and neutropenia (< 1,000 cells/mm3). Anemia occurred in 22% of the neonates who received zidovudine and in 12% of the neonates who received placebo. The mean difference in hemoglobin values was less than 1 g/dL for neonates receiving zidovudine compared with neonates receiving placebo. No neonates with anemia required transfusion and all hemoglobin values spontaneously returned to normal within 6 weeks after completion of therapy with zidovudine. Neutropenia in neonates was reported with similar frequency in the group that received zidovudine (21%) and in the group that received placebo (27%). The long-term consequences of in utero and infant exposure to zidovudine are unknown.
## Postmarketing Experience
- In addition to adverse reactions reported from clinical trials, the following reactions have been identified during post-marketing use of zidovudine. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to zidovudine.
- Body as a Whole: Back pain, chest pain, flu-like syndrome, generalized pain, redistribution/accumulation of body fat.
- Cardiovascular: Cardiomyopathy, syncope.
- Endocrine: Gynecomastia.
- Eye: Macular edema.
- Gastrointestinal: Dysphagia, flatulence, oral mucosa pigmentation, mouth ulcer.
- General: Sensitization reactions including anaphylaxis and angioedema, vasculitis.
- Hemic and Lymphatic: Aplastic anemia, hemolytic anemia, leukopenia, lymphadenopathy, pancytopenia with marrow hypoplasia, pure red cell aplasia.
- Hepatobiliary Tract and Pancreas: Hepatitis, hepatomegaly with steatosis, jaundice, lactic acidosis, pancreatitis.
- Musculoskeletal: Increased CPK, increased LDH, muscle spasm, myopathy and myositis with pathological changes (similar to that produced by HIV-1 disease), rhabdomyolysis, tremor.
- Nervous: Anxiety, confusion, depression, dizziness, loss of mental acuity, mania, paresthesia, seizures, somnolence, vertigo.
- Respiratory: Dyspnea, rhinitis, sinusitis.
- Skin: Changes in skin and nail pigmentation, pruritus, Stevens-Johnson Syndrome, toxic epidermal necrolysis, sweat, urticaria.
- Special Senses: Amblyopia, hearing loss, photophobia, taste perversion.
- Urogenital: Urinary frequency, urinary hesitancy.
# Drug Interactions
Antiretroviral Agents
Stavudine
- Concomitant use of zidovudine with stavudine should be avoided since an antagonistic relationship has been demonstrated in vitro.
Nucleoside Analogues Affecting DNA Replication
- Some nucleoside analogues affecting DNA replication, such as ribavirin, antagonize the in vitro antiviral activity of zidovudine against HIV-1; concomitant use of such drugs should be avoided.
Doxorubicin
- Concomitant use of zidovudine with doxorubicin should be avoided since an antagonistic relationship has been demonstrated in vitro.
Hematologic/Bone Marrow Suppressive/Cytotoxic Agents
- Coadministration of ganciclovir, interferon alfa, ribavirin and other bone marrow suppressive or cytotoxic agents may increase the hematologic toxicity of zidovudine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Teratogenic Effects
- In humans, treatment with zidovudine during pregnancy reduced the rate of maternal-fetal HIV-1 transmission from 24.9% for infants born to placebo-treated mothers to 7.8% for infants born to mothers treated with zidovudine. There were no differences in pregnancy-related adverse events between the treatment groups. Animal reproduction studies in rats and rabbits showed evidence of embryotoxicity and increased fetal malformations.
- A randomized, double-blind, placebo-controlled trial was conducted in HIV-1-infected pregnant women to determine the utility of zidovudine for the prevention of maternal-fetal HIV-1-transmission. Congenital abnormalities occurred with similar frequency between neonates born to mothers who received zidovudine and neonates born to mothers who received placebo. The observed abnormalities included problems in embryogenesis (prior to 14 weeks) or were recognized on ultrasound before or immediately after initiation of study drug.
- Increased fetal resorptions occurred in pregnant rats and rabbits treated with doses of zidovudine that produced drug plasma concentrations 66 to 226 times (rats) and 12 to 87 times (rabbits) the mean steady-state peak human plasma concentration following a single 100 mg dose of zidovudine. There were no other reported developmental anomalies. In another developmental toxicity study, pregnant rats received zidovudine up to near-lethal doses that produced peak plasma concentrations 350 times peak human plasma concentrations (300 times the daily exposure [AUC] in humans given 600 mg/day zidovudine). This dose was associated with marked maternal toxicity and an increased incidence of fetal malformations. However, there were no signs of teratogenicity at doses up to one-fifth the lethal dose.
Antiretroviral Pregnancy Registry
- To monitor maternal-fetal outcomes of pregnant women exposed to zidovudine, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zidovudine in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Zidovudine during labor and delivery.
### Nursing Mothers
- Zidovudine is excreted in human milk. The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breast-feed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving zidovudine.
### Pediatric Use
- Zidovudine has been studied in HIV-1-infected pediatric patients ≥ 6 weeks of age who had HIV-1-related symptoms or who were asymptomatic with abnormal laboratory values indicating significant HIV-1-related immunosuppression. Zidovudine has also been studied in neonates perinatally exposed to HIV-1.
### Geriatic Use
- Clinical studies of zidovudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
### Gender
- There is no FDA guidance on the use of Zidovudine with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Zidovudine with respect to specific racial populations.
### Renal Impairment
- In patients with severely impaired renal function (CrCl < 15 mL/min), dosage reduction is recommended.
### Hepatic Impairment
- Zidovudine is eliminated from the body primarily by renal excretion following metabolism in the liver (glucuronidation). Although the data are limited, zidovudine concentrations appear to be increased in patients with severely impaired hepatic function, which may increase the risk of hematologic toxicity.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Zidovudine in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Zidovudine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Treatment of HIV-1 Infection
Adults
- The recommended oral dose of zidovudine tablets is 600 mg/day in divided doses in combination with other antiretroviral agents.
Pediatric Patients (Aged 4 Weeks to <18 Years)
- Healthcare professionals should pay special attention to accurate calculation of the dose of zidovudine tablets, transcription of the medication order, dispensing information and dosing instructions to minimize risk for medication dosing errors.
- Prescribers should calculate the appropriate dose of zidovudine tablets for each child based on body weight (kg) and should not exceed the recommended adult dose.
- Before prescribing zidovudine tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow a zidovudine tablet, the zidovudine syrup formulation should be prescribed.
- The recommended dosage in pediatric patients 4 weeks of age and older and weighing ≥ 4 kg is provided in Table 1. Zidovudine syrup should be used to provide accurate dosage when whole tablets are not appropriate.
- Alternatively, dosing for zidovudine tablets can be based on body surface area (BSA) for each child. The recommended oral dose of zidovudine tablets is 480 mg/m2/day in divided doses (240 mg/m2 twice daily or 160 mg/m2 three times daily). In some cases the dose calculated by mg/kg will not be the same as that calculated by BSA.
Prevention of Maternal-Fetal HIV-1 Transmission
- The recommended dosage regimen for administration to pregnant women (> 14 weeks of pregnancy) and their neonates is:
Maternal Dosing
- 100 mg orally 5 times per day until the start of labor. During labor and delivery, intravenous zidovudine should be administered at 2 mg/kg (total body weight) over 1 hour followed by a continuous intravenous infusion of 1 mg/kg/hour (total body weight) until clamping of the umbilical cord.
Neonatal Dosing
- Start neonatal dosing within 12 hours after birth and continue through 6 weeks of age. Neonates unable to receive oral dosing may be administered zidovudine intravenously. See Table 2.
Patients with Severe Anemia and/or Neutropenia
- Significant anemia (hemoglobin < 7.5 g/dL or reduction > 25% of baseline) and/or significant neutropenia (granulocyte count < 750 cells/mm3 or reduction > 50% from baseline) may require a dose interruption until evidence of marrow recovery is observed. In patients who develop significant anemia, dose interruption does not necessarily eliminate the need for transfusion. If marrow recovery occurs following dose interruption, resumption in dose may be appropriate using adjunctive measures such as epoetin alfa at recommended doses, depending on hematologic indices such as serum erythropoetin level and patient tolerance.
Patients with Renal Impairment
End-Stage Renal Disease
- In patients maintained on hemodialysis or peritoneal dialysis, the recommended dosage is 100 mg every 6 to 8 hours.
Patients with Hepatic Impairment
- There are insufficient data to recommend dose adjustment of zidovudine tablets in patients with mild to moderate impaired hepatic function or liver cirrhosis.
DOSAGE FORMS AND STRENGTHS
Zidovudine Tablets
- The 300 mg tablets are white to off-white film-coated, round, unscored tablets debossed with M 106 on one side of the tablet and blank on the other side.
### Monitoring
- There is limited information regarding Monitoring of Zidovudine in the drug label.
- Description
# IV Compatibility
- There is limited information regarding IV Compatibility of Zidovudine in the drug label.
# Overdosage
- Acute overdoses of zidovudine have been reported in pediatric patients and adults. These involved exposures up to 50 grams. No specific symptoms or signs have been identified following acute overdosage with zidovudine apart from those listed as adverse events such as fatigue, headache, vomiting and occasional reports of hematological disturbances. All patients recovered without permanent sequelae. Hemodialysis and peritoneal dialysis appear to have a negligible effect on the removal of zidovudine while elimination of its primary metabolite, 3’-azido-3’-deoxy-5’-O-β-D-glucopyranuronosylthymidine (GZDV), is enhanced.
# Pharmacology
## Mechanism of Action
- Zidovudine is an antiviral agent.
## Structure
- Zidovudine (formerly called azidothymidine [AZT]), is a pyrimidine nucleoside analogue active against HIV-1. The chemical name of zidovudine is 3’-Azido-3’-deoxythymidine; it has the following structural formula:
- Zidovudine, USP is a white to yellowish powder with a molecular weight of 267.24 and a solubility of 20.1 mg/mL in water at 25°C. The molecular formula is C10H13N5O4.
- Zidovudine tablets, USP are for oral administration. Each film-coated tablet contains 300 mg of zidovudine, USP and the inactive ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate and titanium dioxide.
## Pharmacodynamics
- There is limited information regarding Pharmacodynamics of Zidovudine in the drug label.
## Pharmacokinetics
Absorption and Bioavailability
- In adults, following oral administration, zidovudine is rapidly absorbed and extensively distributed, with peak serum concentrations occurring within 0.5 to 1.5 hours. The AUC was equivalent when zidovudine was administered as zidovudine tablets or syrup compared with zidovudine capsules. The pharmacokinetic properties of zidovudine in fasting adult patients are summarized in Table 7.
Distribution
- The apparent volume of distribution of zidovudine, following oral administration, is 1.6 ± 0.6 L/kg; and binding to plasma protein is low, < 38% (Table 7).
Metabolism and Elimination
- Zidovudine is primarily eliminated by hepatic metabolism. The major metabolite of zidovudine is GZDV. GZDV AUC is about 3-fold greater than the zidovudine AUC. Urinary recovery of zidovudine and GZDV accounts for 14% and 74%, respectively, of the dose following oral administration. A second metabolite, 3’-amino-3’-deoxythymidine (AMT), has been identified in the plasma following single-dose intravenous (IV) administration of zidovudine. The AMT AUC was one-fifth of the zidovudine AUC. Pharmacokinetics of zidovudine were dose independent at oral dosing regimens ranging from 2 mg/kg every 8 hours to 10 mg/kg every 4 hours.
Effect of Food on Absorption
- Zidovudine may be administered with or without food. The zidovudine AUC was similar when a single dose of zidovudine was administered with food.
Special Populations
Renal Impairment
- Zidovudine clearance was decreased resulting in increased zidovudine and GZDV half-life and AUC in patients with impaired renal function (n = 14) following a single 200 mg oral dose (Table 8). Plasma concentrations of AMT were not determined. A dose adjustment should not be necessary for patients with creatinine clearance (CrCl) ≥ 15 mL/min.
Hemodialysis and Peritoneal Dialysis
- The pharmacokinetics and tolerance of zidovudine were evaluated in a multiple-dose study in patients undergoing hemodialysis (n = 5) or peritoneal dialysis (n = 6) receiving escalating doses up to 200 mg five times daily for 8 weeks. Daily doses of 500 mg or less were well tolerated despite significantly elevated GZDV plasma concentrations. Apparent zidovudine oral clearance was approximately 50% of that reported in patients with normal renal function. Hemodialysis and peritoneal dialysis appeared to have a negligible effect on the removal of zidovudine, whereas GZDV elimination was enhanced. A dosage adjustment is recommended for patients undergoing hemodialysis or peritoneal dialysis.
Hepatic Impairment
- Data describing the effect of hepatic impairment on the pharmacokinetics of zidovudine are limited. However, because zidovudine is eliminated primarily by hepatic metabolism, it is expected that zidovudine clearance would be decreased and plasma concentrations would be increased following administration of the recommended adult doses to patients with hepatic impairment.
Pediatric Patients
- Zidovudine pharmacokinetics have been evaluated in HIV-1-infected pediatric patients (Table 9).
Patients Aged 3 Months to 12 Years
- Overall, zidovudine pharmacokinetics in pediatric patients greater than 3 months of age are similar to those in adult patients. Proportional increases in plasma zidovudine concentrations were observed following administration of oral solution from 90 to 240 mg/m2 every 6 hours. Oral bioavailability, terminal half-life and oral clearance were comparable to adult values. As in adult patients, the major route of elimination was by metabolism to GZDV. After intravenous dosing, about 29% of the dose was excreted in the urine unchanged and about 45% of the dose was excreted as GZDV.
Patients Aged Less Than 3 Months
- Zidovudine pharmacokinetics have been evaluated in pediatric patients from birth to 3 months of life. Zidovudine elimination was determined immediately following birth in eight neonates who were exposed to zidovudine in utero. The half-life was 13 ± 5.8 hours. In neonates ≤ 14 days old, bioavailability was greater, total body clearance was slower and half-life was longer than in pediatric patients > 14 days old. For dose recommendations for neonates.
Pregnancy
- Zidovudine pharmacokinetics have been studied in a Phase I study of eight women during the last trimester of pregnancy. Zidovudine pharmacokinetics were similar to those of nonpregnant adults. Consistent with passive transmission of the drug across the placenta, zidovudine concentrations in neonatal plasma at birth were essentially equal to those in maternal plasma at delivery.
- Although data are limited, methadone maintenance therapy in five pregnant women did not appear to alter zidovudine pharmacokinetics.
Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. After administration of a single dose of 200 mg zidovudine to 13 HIV-1-infected women, the mean concentration of zidovudine was similar in human milk and serum.
Geriatric Patients
- Zidovudine pharmacokinetics have not been studied in patients over 65 years of age.
Gender
- A pharmacokinetic study in healthy male (n = 12) and female (n = 12) subjects showed no differences in zidovudine AUC when a single dose of zidovudine was administered as the 300 mg zidovudine tablet.
Drug Interactions
- [See Drug Interactions].
Phenytoin
- Phenytoin plasma levels have been reported to be low in some patients receiving zidovudine, while in one case a high level was documented. However, in a pharmacokinetic interaction study in which 12 HIV-1-positive volunteers received a single 300 mg phenytoin dose alone and during steady-state zidovudine conditions (200 mg every 4 hours), no change in phenytoin kinetics was observed. Although not designed to optimally assess the effect of phenytoin on zidovudine kinetics, a 30% decrease in oral zidovudine clearance was observed with phenytoin.
Ribavirin
- In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multidrug regimen to HIV-1/HCV co-infected patients.
Microbiology
Mechanism of Action
- Zidovudine is a synthetic nucleoside analogue. Intracellularly, zidovudine is phosphorylated to its active 5’-triphosphate metabolite, zidovudine triphosphate (ZDV-TP). The principal mode of action of ZDV-TP is inhibition of reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue. ZDV-TP is a weak inhibitor of the cellular DNA polymerases α and γ and has been reported to be incorporated into the DNA of cells in culture.
Antiviral Activity
- The antiviral activity of zidovudine against HIV-1 was assessed in a number of cell lines (including monocytes and fresh human peripheral blood lymphocytes). The EC50 and EC90 values for zidovudine were 0.01 to 0.49 µM (1 µM = 0.27 mcg/mL) and 0.1 to 9 µM, respectively. HIV-1 from therapy-naive subjects with no mutations associated with resistance gave median EC50 values of 0.011 µM (range: 0.005 to 0.110 µM) from Virco (n = 92 baseline samples from COL40263) and 0.0017 µM (0.006 to 0.0340 µM) from Monogram Biosciences (n = 135 baseline samples from ESS30009). The EC50 values of zidovudine against different HIV-1 clades (A-G) ranged from 0.00018 to 0.02 µM, and against HIV-2 isolates from 0.00049 to 0.004 µM. In cell culture drug combination studies, zidovudine demonstrates synergistic activity with the nucleoside reverse transcriptase inhibitors abacavir, didanosine and lamivudine; the non-nucleoside reverse transcriptase inhibitors delavirdine and nevirapine; and the protease inhibitors indinavir, nelfinavir, ritonavir, and saquinavir; and additive activity with interferon alfa. Ribavirin has been found to inhibit the phosphorylation of zidovudine in cell culture.
Resistance
- Genotypic analyses of the isolates selected in cell culture and recovered from zidovudine-treated patients showed mutations in the HIV-1 RT gene resulting in six amino acid substitutions (M41L, D67N, K70R, L210W, T215Y or F, and K219Q) that confer zidovudine resistance. In general, higher levels of resistance were associated with greater number of amino acid substitutions. In some patients harboring zidovudine-resistant virus at baseline, phenotypic sensitivity to zidovudine was restored by 12 weeks of treatment with lamivudine and zidovudine. Combination therapy with lamivudine plus zidovudine delayed the emergence of substitutions conferring resistance to zidovudine.
Cross-resistance
- In a study of 167 HIV-1-infected patients, isolates (n = 2) with multidrug resistance to didanosine, lamivudine, stavudine, zalcitabine and zidovudine were recovered from patients treated for ≥ 1 year with zidovudine plus didanosine or zidovudine plus zalcitabine. The pattern of resistance-associated amino acid substitutions with such combination therapies was different (A62V, V75I, F77L, F116Y, Q151M) from the pattern with zidovudine monotherapy, with the Q151M substitution being most commonly associated with multidrug resistance. The substitution at codon 151 in combination with substitutions at 62, 75, 77 and 116 results in a virus with reduced susceptibility to didanosine, lamivudine, stavudine, zalcitabine and zidovudine. Thymidine analogue mutations (TAMs) are selected by zidovudine and confer cross-resistance to abacavir, didanosine, stavudine, tenofovir and zalcitabine.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Zidovudine was administered orally at three dosage levels to separate groups of mice and rats (60 females and 60 males in each group). Initial single daily doses were 30, 60 and 120 mg/kg/day in mice and 80, 220 and 600 mg/kg/day in rats. The doses in mice were reduced to 20, 30 and 40 mg/kg/day after day 90 because of treatment-related anemia, whereas in rats only the high dose was reduced to 450 mg/kg/day on day 91 and then to 300 mg/kg/day on day 279.
- In mice, seven late-appearing (after 19 months) vaginal neoplasms (five nonmetastasizing squamous cell carcinomas, one squamous cell papilloma and one squamous polyp) occurred in animals given the highest dose. One late-appearing squamous cell papilloma occurred in the vagina of a middle-dose animal. No vaginal tumors were found at the lowest dose.
- In rats, two late-appearing (after 20 months), nonmetastasizing vaginal squamous cell carcinomas occurred in animals given the highest dose. No vaginal tumors occurred at the low or middle dose in rats. No other drug-related tumors were observed in either sex of either species.
- At doses that produced tumors in mice and rats, the estimated drug exposure (as measured by AUC) was approximately 3 times (mouse) and 24 times (rat) the estimated human exposure at the recommended therapeutic dose of 100 mg every 4 hours.
- It is not known how predictive the results of rodent carcinogenicity studies may be for humans.
- Zidovudine was mutagenic in a 5178Y/TK+/- mouse lymphoma assay, positive in an in vitro cell transformation assay, clastogenic in a cytogenetic assay using cultured human lymphocytes, and positive in mouse and rat micronucleus tests after repeated doses. It was negative in a cytogenetic study in rats given a single dose.
- Zidovudine, administered to male and female rats at doses up to 7 times the usual adult dose based on body surface area, had no effect on fertility judged by conception rates.
- Two transplacental carcinogenicity studies were conducted in mice. One study administered zidovudine at doses of 20 mg/kg/day or 40 mg/kg/day from gestation day 10 through parturition and lactation with dosing continuing in offspring for 24 months postnatally. The doses of zidovudine administered in this study produced zidovudine exposures approximately 3 times the estimated human exposure at recommended doses. After 24 months, an increase in incidence of vaginal tumors was noted with no increase in tumors in the liver or lung or any other organ in either gender. These findings are consistent with results of the standard oral carcinogenicity study in mice, as described earlier. A second study administered zidovudine at maximum tolerated doses of 12.5 mg/day or 25 mg/day (~1000 mg/kg nonpregnant body weight or ~ 450 mg/kg of term body weight) to pregnant mice from days 12 through 18 of gestation. There was an increase in the number of tumors in the lung, liver and female reproductive tracts in the offspring of mice receiving the higher dose level of zidovudine.
Reproductive and Developmental Toxicology Studies
- Oral teratology studies in the rat and in the rabbit at doses up to 500 mg/kg/day revealed no evidence of teratogenicity with zidovudine. Zidovudine treatment resulted in embryo/fetal toxicity as evidenced by an increase in the incidence of fetal resorptions in rats given 150 or 450 mg/kg/day and rabbits given 500 mg/kg/day. The doses used in the teratology studies resulted in peak zidovudine plasma concentrations (after one-half of the daily dose) in rats 66 to 226 times, and in rabbits 12 to 87 times, mean steady-state peak human plasma concentrations (after one-sixth of the daily dose) achieved with the recommended daily dose (100 mg every 4 hours). In an in vitro experiment with fertilized mouse oocytes, zidovudine exposure resulted in a dose dependent reduction in blastocyst formation. In an additional teratology study in rats, a dose of 3000 mg/kg/day (very near the oral median lethal dose in rats of 3683 mg/kg) caused marked maternal toxicity and an increase in the incidence of fetal malformations. This dose resulted in peak zidovudine plasma concentrations 350 times peak human plasma concentrations. (Estimated AUC in rats at this dose level was 300 times the daily AUC in humans given 600 mg/day.) No evidence of teratogenicity was seen in this experiment at doses of 600 mg/kg/day or less.
# Clinical Studies
- Therapy with zidovudine has been shown to prolong survival and decrease the incidence of opportunistic infections in patients with advanced HIV-1 disease and to delay disease progression in asymptomatic HIV-1-infected patients.
Adults
Combination Therapy
- Zidovudine in combination with other antiretroviral agents has been shown to be superior to monotherapy for one or more of the following endpoints: delaying death, delaying development of AIDS, increasing CD4+ cell counts, and decreasing plasma HIV-1 RNA.
- The clinical efficacy of a combination regimen that includes zidovudine was demonstrated in study ACTG 320. This study was a multi-center, randomized, double-blind, placebo-controlled trial that compared zidovudine 600 mg/day plus EPIVIR®* 300 mg/day to zidovudine plus EPIVIR®* plus indinavir 800 mg three times daily. The incidence of AIDS-defining events or death was lower in the triple-drug–containing arm compared with the 2-drug–containing arm (6.1% vs. 10.9%, respectively).
Monotherapy
- In controlled studies of treatment-naive patients conducted between 1986 and 1989, monotherapy with zidovudine, as compared with placebo, reduced the risk of HIV-1 disease progression, as assessed using endpoints that included the occurrence of HIV-1-related illnesses, AIDS-defining events, or death. These studies enrolled patients with advanced disease (BW 002), and asymptomatic or mildly symptomatic disease in patients with CD4+ cell counts between 200 and 500 cells/mm3 (ACTG 016 and ACTG 019). A survival benefit for monotherapy with zidovudine was not demonstrated in the latter two studies. Subsequent studies showed that the clinical benefit of monotherapy with zidovudine was time limited.
Pediatric Patients
- ACTG 300 was a multi-center, randomized, double-blind study that provided for comparison of EPIVIR®* plus zidovudine to didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive pediatric patients were enrolled in these two treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), the mean baseline CD4+ cell count was 868 cells/mm3, and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration that patients remained on study was approximately 10 months. Results are summarized in Table 11.
Prevention of Maternal-Fetal HIV-1 Transmission
- The utility of zidovudine for the prevention of maternal-fetal HIV-1 transmission was demonstrated in a randomized, double-blind, placebo-controlled trial (ACTG 076) conducted in HIV-1-infected pregnant women with CD4+ cell counts of 200 to 1,818 cells/mm3 (median in the treated group: 560 cells/mm3) who had little or no previous exposure to zidovudine. Oral zidovudine was initiated between 14 and 34 weeks of gestation (median 11 weeks of therapy) followed by IV administration of zidovudine during labor and delivery. Following birth, neonates received oral zidovudine syrup for 6 weeks. The study showed a statistically significant difference in the incidence of HIV-1 infection in the neonates (based on viral culture from peripheral blood) between the group receiving zidovudine and the group receiving placebo. Of 363 neonates evaluated in the study, the estimated risk of HIV-1 infection was 7.8% in the group receiving zidovudine and 24.9% in the placebo group, a relative reduction in transmission risk of 68.7%. Zidovudine was well tolerated by mothers and infants. There was no difference in pregnancy-related adverse events between the treatment groups.
# How Supplied
- Zidovudine Tablets, USP are available containing 300 mg of zidovudine, USP.
- The 300 mg tablets are white to off-white film-coated, round, unscored tablets debossed with M 106 on one side of the tablet and blank on the other side. They are available as follows:
- NDC 0378-6106-91
- bottles of 60 tablets
## Storage
- Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]
- Protect from moisture.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advice for the Patient
Neutropenia and Anemia
- Patients should be informed that the major toxicities of zidovudine are neutropenia and/or anemia. The frequency and severity of these toxicities are greater in patients with more advanced disease and in those who initiate therapy later in the course of their infection. Patients should be informed that if toxicity develops, they may require transfusions or drug discontinuation. Patients should be informed of the extreme importance of having their blood counts followed closely while on therapy, especially for patients with advanced symptomatic HIV-1 disease.
Myopathy
- Patients should be informed that myopathy and myositis with pathological changes, similar to that produced by HIV-1 disease, have been associated with prolonged use of zidovudine.
Lactic Acidosis/Hepatomegaly
- Patients should be informed that some HIV medicines, including zidovudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly).
HIV-1/HCV Co-infection
- Patients with HIV-1/HCV co-infection should be informed that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin .
Use with Other Zidovudine-containing Products
- Zidovudine tablets should not be administered with combination products that contain zidovudine as one of their components (e.g., COMBIVIR®* [lamivudine and zidovudine] Tablets or TRIZIVIR®* [abacavir sulfate, lamivudine and zidovudine] Tablets).
Redistribution/Accumulation of Body Fat
- Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Common Adverse Reactions
- Patients should be informed that the most commonly reported adverse reactions in adult patients being treated with zidovudine were headache, malaise, nausea, anorexia and vomiting. The most commonly reported adverse reactions in pediatric patients receiving zidovudine were fever, cough and digestive disorders. Patients also should be encouraged to contact their physician if they experience muscle weakness, shortness of breath, symptoms of hepatitis or pancreatitis, or any other unexpected adverse events while being treated with zidovudine.
Drug Interactions
- Patients should be cautioned about the use of other medications, including ganciclovir, interferon alfa and ribavirin, which may exacerbate the toxicity of zidovudine.
Pregnancy
- Pregnant women considering the use of zidovudine during pregnancy for prevention of HIV-1 transmission to their infants should be informed that transmission may still occur in some cases despite therapy. The long-term consequences of in utero and infant exposure to zidovudine are unknown, including the possible risk of cancer.
- HIV-1-infected pregnant women should be informed not to breast-feed to avoid postnatal transmission of HIV to a child who may not yet be infected.
Information About HIV-1 Infection
- Ziduvine is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using zidovudine tablets.
- Patients should be advised to avoid doing things that can spread HIV-1 infection to others.
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions or blood.
- Do not breast-feed. Zidovudine is excreted in human breast milk. Mothers with HIV-1 should not breast-feed because HIV-1 can be passed to the baby in the breast milk.
- Patients should be informed to take all HIV medications exactly as prescribed.
# Precautions with Alcohol
- Alcohol-Zidovudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Retrovir
# Look-Alike Drug Names
There is limited information regarding Zidovudine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/AZT | |
f103fe6685de7df97643d5b4afc4a3f433ed5321 | wikidoc | Abagovomab | Abagovomab
# Overview
Abagovomab is a mouse anti-idiotype monoclonal antibody whose variable epitope mirrors a tumour antigen (CA-125) highly expressed in the epithelial ovarian cancer. Abagovomab does not bind directly to CA-125, but it works as a "surrogate" antigen, enabling the immune system to identify and attack tumour cells displaying the CA 125 protein. Through this, it is hoped that the body's immune system may be able to combat any remaining individual tumour cells and thus prevent recurrence of the disease.
# Curent Status
Abagovomab is currently under clinical development in patients with advanced ovarian cancer, as consolidation of the remission status obtained following surgery and standard platinum and taxane first line chemotherapy.
# Phase II
In a Phase II study on 119 patients with advanced ovarian cancer in which the standard therapies had already been ineffective, treatment with abagovomab led to a prolongation of survival time (23.4 months compared to 4.9 months) in those patients who responded to the vaccination, i.e. those in whom the formation of antibodies against the tumour was proven (almost 70 % of patients).
The vaccine showed hardly any side effects in preliminary studies.
# Ovarian Cancer
Ovarian cancer is the most malignant tumour of the female reproductive organs. After endometrial cancer, it is the second most common genital tumour in women with approximately 9,000 women newly affected each year and, because of its aggressiveness, it has the highest mortality rate. This is due in part to the fact that there is no screening examination for early detection, and that the disease is therefore usually only discovered at an advanced stage, and in part to the tumour's tendency, although responding well to initial treatment, to recur again later.
In spite of initially successful treatment with surgery and chemotherapy, which forces back the tumour "completely", i.e. into no longer visible residues, there is a relapse of the disease (recurrence) in more than half the women affected. Today, no further therapy would be conducted in this situation as long as the disease did not occur again, i.e. clinical monitoring of the symptom-free patients as part of follow-up care is the current standard procedure.
In this time-window of the patient’s hystory so called ‘watch and wait’ abagovomab is potentially capable of deferring or even preventing the occurrence of the relapse.
# Developement
Abagovomab has been developed by the pharmaceutical company Menarini. A multicenter clinical trial, internationally known as MIMOSA (Monoclonal antibody Immunotherapy for Malignancies of the Ovary by Subcutaneous Abagovomab), in which Abagovomab will be administered as maintenance therapy (after first line therapy with surgery and chemotherapy), is ongoing in patients with ovarian cancer.
Nine hundred women in whom the ovarian tumour was removed by surgery and standard chemotherapy with paclitaxel und carboplatin can be enrolled in the MIMOSA study, involving eight countries throughout the world (Germany, USA, Italy, Poland, Czech Republic, Spain, Hungary and Belgium) in more than 120 experienced clinical sites.
# Further reading
- Wagner U, Kohler S, Reinartz S, Giffels P, Huober J, Renke K, Schlebusch H, Biersack HJ, Mobus V, Kreienberg R, Bauknecht T, Krebs D, Wallwiener D. Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. Clin Cancer Res. 2001;7(5):1154-62.
- Reinartz S, Kohler S, Schlebusch H, Krista K, Giffels P, Renke K, Huober J, Mobus V, Kreienberg R, DuBois A, Sabbatini P, Wagner U. Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II). Clin Cancer Res. 2004;10(5):1580-7.
- Pfisterer J, du Bois A, Sehouli J, Loibl S, Reinartz S, Reuß A, Canzler U, Belau A, Jackisch C, Kimmig R, Wollschlaeger K, Heilmann V, Hilpert F. The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of the AGO-OVAR. Ann Oncol. 2006;17(10):1568-77.
- Sabbatini P, Dupont J, Aghajanian C, Derosa F, Poynor E, Anderson S, Hensley M, Livingston P, Iosonos A, Spriggs D, McGuire W, Reinartz S, Schneider S, Grande C, Lele S, Rodabaugh K, Kepner J, Ferrone S, Odunsi K. Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Clin Cancer Res. 2006;12(18):5503-10. | Abagovomab
Template:Drugbox-mab
# Overview
Abagovomab is a mouse anti-idiotype monoclonal antibody whose variable epitope mirrors a tumour antigen (CA-125) highly expressed in the epithelial ovarian cancer. Abagovomab does not bind directly to CA-125, but it works as a "surrogate" antigen, enabling the immune system to identify and attack tumour cells displaying the CA 125 protein. Through this, it is hoped that the body's immune system may be able to combat any remaining individual tumour cells and thus prevent recurrence of the disease.
# Curent Status
Abagovomab is currently under clinical development in patients with advanced ovarian cancer, as consolidation of the remission status obtained following surgery and standard platinum and taxane first line chemotherapy.
# Phase II
In a Phase II study on 119 patients with advanced ovarian cancer in which the standard therapies had already been ineffective, treatment with abagovomab led to a prolongation of survival time (23.4 months compared to 4.9 months) in those patients who responded to the vaccination, i.e. those in whom the formation of antibodies against the tumour was proven (almost 70 % of patients).
The vaccine showed hardly any side effects in preliminary studies.
# Ovarian Cancer
Ovarian cancer is the most malignant tumour of the female reproductive organs. After endometrial cancer, it is the second most common genital tumour in women with approximately 9,000 women newly affected each year and, because of its aggressiveness, it has the highest mortality rate. This is due in part to the fact that there is no screening examination for early detection, and that the disease is therefore usually only discovered at an advanced stage, and in part to the tumour's tendency, although responding well to initial treatment, to recur again later.
In spite of initially successful treatment with surgery and chemotherapy, which forces back the tumour "completely", i.e. into no longer visible residues, there is a relapse of the disease (recurrence) in more than half the women affected. Today, no further therapy would be conducted in this situation as long as the disease did not occur again, i.e. clinical monitoring of the symptom-free patients as part of follow-up care is the current standard procedure.
In this time-window of the patient’s hystory so called ‘watch and wait’ abagovomab is potentially capable of deferring or even preventing the occurrence of the relapse.
# Developement
Abagovomab has been developed by the pharmaceutical company Menarini. A multicenter clinical trial, internationally known as MIMOSA (Monoclonal antibody Immunotherapy for Malignancies of the Ovary by Subcutaneous Abagovomab), in which Abagovomab will be administered as maintenance therapy (after first line therapy with surgery and chemotherapy), is ongoing in patients with ovarian cancer.
Nine hundred women in whom the ovarian tumour was removed by surgery and standard chemotherapy with paclitaxel und carboplatin can be enrolled in the MIMOSA study, involving eight countries throughout the world (Germany, USA, Italy, Poland, Czech Republic, Spain, Hungary and Belgium) in more than 120 experienced clinical sites.
# Further reading
- Wagner U, Kohler S, Reinartz S, Giffels P, Huober J, Renke K, Schlebusch H, Biersack HJ, Mobus V, Kreienberg R, Bauknecht T, Krebs D, Wallwiener D. Immunological consolidation of ovarian carcinoma recurrences with monoclonal anti-idiotype antibody ACA125: immune responses and survival in palliative treatment. Clin Cancer Res. 2001;7(5):1154-62. http://clincancerres.aacrjournals.org/cgi/content/full/7/5/1154
- Reinartz S, Kohler S, Schlebusch H, Krista K, Giffels P, Renke K, Huober J, Mobus V, Kreienberg R, DuBois A, Sabbatini P, Wagner U. Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: immunological response and survival (phase Ib/II). Clin Cancer Res. 2004;10(5):1580-7. http://clincancerres.aacrjournals.org/cgi/content/full/10/5/1580
- Pfisterer J, du Bois A, Sehouli J, Loibl S, Reinartz S, Reuß A, Canzler U, Belau A, Jackisch C, Kimmig R, Wollschlaeger K, Heilmann V, Hilpert F. The anti-idiotypic antibody abagovomab in patients with recurrent ovarian cancer. A phase I trial of the AGO-OVAR. Ann Oncol. 2006;17(10):1568-77. http://annonc.oxfordjournals.org/cgi/content/abstract/17/10/1568
- Sabbatini P, Dupont J, Aghajanian C, Derosa F, Poynor E, Anderson S, Hensley M, Livingston P, Iosonos A, Spriggs D, McGuire W, Reinartz S, Schneider S, Grande C, Lele S, Rodabaugh K, Kepner J, Ferrone S, Odunsi K. Phase I study of abagovomab in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Clin Cancer Res. 2006;12(18):5503-10. http://clincancerres.aacrjournals.org/cgi/content/abstract/12/18/5503
# External links
- Menarini page about abagovomab
- Menarini page about MIMOSA project
- Clinical trial MIMOSA
- Clinical trial MIMOSA
Template:Mousemonoclonals
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Abagovomab | |
ac19d7936faf58d555c3beb5001bf30637c522ec | wikidoc | Abfraction | Abfraction
# Overview
Abfraction is the loss of tooth structure from flexural forces. This has not been supported yet by dental research but it is hypothesized that enamel, especially at the cementoenamel junction (CEJ), undergo this pattern of destruction by separating the enamel rods.
As teeth flex under pressure, the arrangement of teeth touching each other, known as occlusion, causes tension on one side of the tooth and compression on the other side of the tooth. This is believed to cause V-shaped depressions on the side under tension and C-shaped depressions on the side under compression.
This theory does not fully satisfy many researchers because there are many teeth whose occlusion causes tension and compression on either side. Consequently, it would be expected that many more teeth would show signs of abfraction, but this is not the case. Research is ongoing to identify the role abfraction has on this pattern of tooth destruction. | Abfraction
# Overview
Abfraction is the loss of tooth structure from flexural forces. This has not been supported yet by dental research but it is hypothesized that enamel, especially at the cementoenamel junction (CEJ), undergo this pattern of destruction by separating the enamel rods.
As teeth flex under pressure, the arrangement of teeth touching each other, known as occlusion, causes tension on one side of the tooth and compression on the other side of the tooth. This is believed to cause V-shaped depressions on the side under tension and C-shaped depressions on the side under compression.
This theory does not fully satisfy many researchers because there are many teeth whose occlusion causes tension and compression on either side. Consequently, it would be expected that many more teeth would show signs of abfraction, but this is not the case. Research is ongoing to identify the role abfraction has on this pattern of tooth destruction. | https://www.wikidoc.org/index.php/Abfraction | |
fbd31b1bd186f824368a866b234ec77b10811c43 | wikidoc | Abiciximab | Abiciximab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Abiciximab is a Platelet aggregation inhibitor that is FDA approved for the {{{indicationType}}} of prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Common adverse reactions include Chest pain , Hypotension ,Injection site pain ,Abdominal pain , Nausea, Vomiting Bleeding
Backache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- initial dosage: 0.25 mg/kg IV bolus (10-60 minutes before the start of PCI)
- maitaining dosage: 0.125 mg/kg/min IV for 12 hours (max 10 ug/min)
- Dosing Information
- initial dosage: 0.25 mg/kg IV (10-60 minutes before the start of PCI)
- maitaining dosage: 10 ug/min IV for 18- 24h (concluding one hour after the PCI)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Level of Evidence: Level A
- Recommendation
- initial dosage: 0.25 mg/kg IV bolus (over 5 minutes)
- maitaing dosage: 10 ug/min IV (continued for 12 hours unless complications developed)
### Non–Guideline-Supported Use
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Abiciximab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Non–Guideline-Supported Use
- Dosing information
- loading dose: 0.25 mg/kg IV
- follow-up: 0.125 mg/min IV for 12h
# Contraindications
Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations:
- Active internal bleeding
- Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of clinical significance.
- History of cerebrovascular accident (CVA) within two years, or CVA with a significant residual neurological deficit
- Bleeding diathesis
- Administration of oral anticoagulants within seven days unless prothrombin time is <1.2 times control
- Thrombocytopenia (<100,000 cells/mL)
- Recent (within six weeks) major surgery or trauma
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Severe uncontrolled hypertension
- Presumed or documented history of vasculitis
- Use of intravenous dextran before PCI, or intent to use it during an intervention
Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins.
# Warnings
Abciximab has the potential to increase the risk of bleeding events, rarely including those with a fatal outcome, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants, or thrombolytics (see ADVERSE REACTIONS: Bleeding).
The risk of major bleeds due to Abciximab therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits.
Should serious bleeding occur that is not controllable with pressure, the infusion of Abciximab and any concomitant heparin should be stopped.
Allergic reactions, some of which were anaphylaxis (sometimes fatal), have been reported rarely in patients treated with ReoPro. Patients with allergic reactions should receive appropriate treatment. Treatment of anaphylaxis should include immediate discontinuation of ReoPro administration and initiation of resuscitative measures.
## Precautions
To minimize the risk of bleeding with Abciximab, it is important to use a low-dose, weight-adjusted heparin regimen, a weight-adjusted Abciximab bolus and infusion, strict anticoagulation guidelines, careful vascular access site management, discontinuation of heparin after the procedure and early femoral arterial sheath removal.
Therapy with Abciximab requires careful attention to all potential bleeding sites including catheter insertion sites, arterial and venous puncture sites, cutdown sites, needle puncture sites, and gastrointestinal, genitourinary, pulmonary (alveolar), and retroperitoneal sites.
Arterial and venous punctures, intramuscular injections, and use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings.
Arterial access site care is important to prevent bleeding. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Femoral vein sheath placement should be avoided unless needed. While the vascular sheath is in place, patients should be maintained on complete bed rest with the head of the bed ≤ 30° and the affected limb restrained in a straight position. Patients may be medicated for back/groin pain as necessary.
Discontinuation of heparin immediately upon completion of the procedure and removal of the arterial sheath within six hours is strongly recommended if APTT ≤ 50 sec or ACT≤ 175 sec (see PRECAUTIONS: Laboratory Tests). In all circumstances, heparin should be discontinued at least two hours prior to arterial sheath removal.
Following sheath removal, pressure should be applied to the femoral artery for at least 30 minutes using either manual compression or a mechanical device for hemostasis. A pressure dressing should be applied following hemostasis. The patient should be maintained on bed rest for six to eight hours following sheath removal or discontinuation of Abciximab, or four hours following discontinuation of heparin, whichever is later. The pressure dressing should be removed prior to ambulation. The sheath insertion site and distal pulses of affected leg(s) should be frequently checked while the femoral artery sheath is in place and for six hours after femoral artery sheath removal. Any hematoma should be measured and monitored for enlargement.
The following conditions have been associated with an increased risk of bleeding and may be additive with the effect of Abciximab in the angioplasty setting: PCI within 12 hours of the onset of symptoms for acute myocardial infarction, prolonged PCI (lasting more than 70 minutes) and failed PCI.
In the EPIC, EPILOG, CAPTURE, and EPISTENT trials, Abciximab was used concomitantly with heparin and aspirin.
For details of the anticoagulation algorithms used in these clinical trials, see CLINICAL STUDIES: Anticoagulation. Because Abciximab inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory drugs, dipyridamole, and ticlopidine.
In the EPIC trial, there was limited experience with the administration of Abciximab with low molecular weight dextran. Low molecular weight dextran was usually given for the deployment of a coronary stent, for which oral anticoagulants were also given. In the 11 patients who received low molecular weight dextran with Abciximab, five had major bleeding events and four had minor bleeding events. None of the five placebo patients treated with low molecular weight dextran had a major or minor bleeding event (see CONTRAINDICATIONS).
Because of observed synergistic effects on bleeding, Abciximab therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with acute myocardial infarction to treatment with combined Abciximab and half-dose Reteplase, or full-dose Reteplase alone (15). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving Abciximab and half-dose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively).
Thrombocytopenia, including severe thrombocytopenia, has been observed with Abciximab administration (see ADVERSE REACTIONS: Thrombocytopenia). Platelet counts should be monitored prior to, during, and after treatment with Abciximab. Acute decreases in platelet count should be differentiated between true thrombocytopenia and pseudothrombocytopenia (see PRECAUTIONS: Laboratory Tests). If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated.
In clinical trials, patients who developed thrombocytopenia were followed with daily platelet counts until their platelet count returned to normal. Heparin and aspirin were discontinued for platelet counts below 60,000 cells/μL and platelets were transfused for a platelet count below 50,000 cells/μL. Most cases of severe thrombocytopenia (< 50,000 cells/μL) occurred within the first 24 hours of Abciximab administration.
In a registry study of Abciximab readministration, a history of thrombocytopenia associated with prior use of Abciximab was predictive of an increased risk of recurrent thrombocytopenia (see ADVERSE REACTIONS: Thrombocytopenia). Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration.
Restoration of Platelet Function- In the event of serious uncontrolled bleeding or the need for emergency surgery, Abciximab should be discontinued. If platelet function does not return to normal, it may be restored, at least in part, with platelet transfusions.
Before infusion of Abciximab, prothrombin time, ACT, APTT, and platelet count should be measured to identify pre-existing hemostatic abnormalities.
Based on an integrated analysis of data from all studies, the following guidelines may be utilized to minimize the risk for bleeding:
- When Abciximab is initiated 18 to 24 hours before PCI, the APTT should be maintained between 60 and 85 seconds during the Abciximab and heparin infusion period.
- During PCI the ACT should be maintained between 200 and 300 seconds.
- If anticoagulation is continued in these patients following PCI, the APTT should be maintained between 55 and 75 seconds.
- The APTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless APTT ≤ 50 seconds or ACT ≤ 175 seconds.
- Platelet counts should be monitored prior to treatment, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal.
- To exclude pseudothrombocytopenia, a laboratory artifact due to in vitro anticoagulant interaction, blood samples should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively. A low platelet count in EDTA but not in heparin and/or citrate is supportive of a diagnosis of pseudothrombocytopenia.
Administration of Abciximab may result in the formation of HACA that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of Abciximab (see WARNINGS: Allergic Reactions; see ADVERSE REACTIONS: Immunogenicity).
Readministration of Abciximab to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second
Abciximab exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the readministration was 6% and increased to 27% post-readministration. There were no reports of serious allergic reactions or anaphylaxis (see WARNINGS: Allergic Reactions). Thrombocytopenia was observed at higher rates in the readministration study than in the phase 3 studies of first-time administration (see PRECAUTIONS: Thrombocytopenia and Adverse Reactions: Thrombocytopenia), suggesting that readministration may be associated with an increased incidence and severity of thrombocytopenia.
# Adverse Reactions
## Clinical Trials Experience
### Bleeding
Abciximab has the potential to increase the risk of bleeding, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants or thrombolytics. Bleeding in the Phase 3 trials was classified as major, minor or insignificant by the criteria of the Thrombolysis in Myocardial Infarction study group (16). Major bleeding events were defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of more than 3 g/dL, or a decrease in hemoglobin of at least 4 g/dL without an identified bleeding site. Insignificant bleeding events were defined as a decrease in hemoglobin of less than 3 g/dL or a decrease in hemoglobin between 3-4 g/dL without observed bleeding. In patients who received transfusions, the number of units of blood lost was estimated through an adaptation of the method of Landefeld, et al. (17).
In the EPIC trial, in which a non-weight-adjusted, longer-duration heparin dose regimen was used, the most common complication during Abciximab therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were significantly increased. Major bleeding occurred in 10.6% of patients in the Abciximab bolus plus infusion arm compared with 3.3% of patients in the placebo arm. Minor bleeding was seen in 16.8% of Abciximab bolus plus infusion patients and 9.2% of placebo patients (7). Approximately 70% of Abciximab-treated patients with major bleeding had bleeding at the arterial access site in the groin. Abciximab-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites.
Bleeding rates were reduced in the CAPTURE trial, and further reduced in the EPILOG and EPISTENT trials by use of modified dosing regimens and specific patient management techniques. In EPILOG and EPISTENT, using the heparin and Abciximab dosing, sheath removal and arterial access site guidelines described under PRECAUTIONS, the incidence of major bleeding in patients treated with Abciximab and low-dose, weight-adjusted heparin was not significantly different from that in patients receiving placebo.
Subgroup analyses in the EPIC and CAPTURE trials showed that non-CABG major bleeding was more common in Abciximab patients weighing ≤ 75 kg. In the EPILOG and EPISTENT trials, which used weight-adjusted heparin dosing, the non-CABG major bleeding rates for Abciximab-treated patients did not differ substantially by weight subgroup.
Although data are limited, Abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. (The range among all treatment arms was 3-5% in EPIC, and 1-2% in the CAPTURE, EPILOG, and EPISTENT trials.) Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. (see PRECAUTIONS: Restoration of Platelet Function.)
The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the CAPTURE, EPILOG, and EPISTENT trials are shown in Table 4. The rates of insignificant bleeding events are not included in Table 4.
Cases of fatal bleeding have been reported rarely during post-marketing use of Abciximab (see WARNINGS: Bleeding Events).
Pulmonary alveolar hemorrhage has been rarely reported during use of Abciximab. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin.
### Intracranial Hemorrhage and Stroke
The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all four trials was not significantly different, 9/3023 for placebo patients and 15/4680 for Abciximab-treated patients. The incidence of intracranial hemorrhage was 3/3023 for placebo patients and 7/4680 for Abciximab patients.
### Thrombocytopenia
In the clinical trials, patients treated with Abciximab were more likely than patients treated with placebo to experience decreases in platelet counts.
Among patients in the EPILOG and EPISTENT trials who were treated with Abciximab plus low-dose heparin, the proportion of patients with any thrombocytopenia (platelets less than 100,000 cells/μL) ranged from 2.5 to 3.0%. The incidence of severe thrombocytopenia (platelets less than 50,000 cells/μL) ranged from 0.4 to 1.0% and platelet transfusions were required in 0.9 to 1.1%, respectively. Modestly lower rates were observed among patients treated with placebo plus standard-dose heparin. Overall higher rates were observed among patients in the EPIC and CAPTURE trials treated with Abciximab plus longer duration heparin: 2.6 to 5.2% were found to have any thrombocytopenia, 0.9 to 1.7% had severe thrombocytopenia, and 2.1 to 5.5% required platelet transfusion, respectively.
In a readministration registry study of patients receiving a second or subsequent exposure to Abciximab (see PRECAUTIONS: Readministration) the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous Abciximab exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.
Among 14 patients who had thrombocytopenia associated with a prior exposure to Abciximab, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe.
### Allergic Reactions
There have been rare reports of allergic reactions, some of which were anaphylaxis (see WARNINGS: Allergic Reactions).
### Other Adverse Reactions
Table 5 shows adverse events other than bleeding and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in patients in the bolus plus infusion arm at an incidence of more than 0.5% higher than in those treated with placebo.
The following additional adverse events from the EPIC, EPILOG and CAPTURE trials were reported by investigators for patients treated with a bolus plus infusion of Abciximab at incidences which were less than 0.5% higher than for patients in the placebo arm.
Cardiovascular System: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%), palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), complete AV block (0.1%), embolism (limb)(0.1%); thrombophlebitis (0.1%);
Gastrointestinal System: dyspepsia (2.1%), diarrhea (1.1%), ileus (0.1%), gastroesophogeal reflux (0.1%);
Hemic and Lymphatic System: anemia (1.3%), leukocytosis (0.5%), petechiae (0.2%);
Nervous System: dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%) muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), diplopia (0.1%);
Respiratory System: pneumonia (0.4%), rales (0.4%), pleural effusion (0.3%), bronchitis (0.3%) bronchospasm (0.3%), pleurisy (0.2%), pulmonary embolism (0.2%), rhonchi (0.1%);
Musculoskeletal System: myalgia (0.2%);
Urogenital System: urinary retention (0.7%), dysuria (0.4%), abnormal renal function (0.4%), frequent micturition (0.1%), cystalgia (0.1%), urinary incontinence (0.1%), prostatitis (0.1%);
Miscellaneous: pain (5.4%), sweating increased (1.0%), asthenia (0.7%), incisional pain (0.6%), pruritus (0.5%), abnormal vision (0.3%), edema (0.3%), wound (0.2%), abscess (0.2%), cellulitis (0.2%), peripheral coldness (0.2%), injection site pain (0.1%), dry mouth (0.1%), pallor (0.1%), diabetes mellitus (0.1%), hyperkalemia (0.1%), enlarged abdomen (0.1%), bullous eruption (0.1%), inflammation (0.1%), drug toxicity (0.1%).
### Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. In the EPIC, EPILOG, and CAPTURE trials, positive HACA responses occurred in approximately 5.8% of these patients receiving a first exposure to Abciximab. No increase in hypersensitivity or allergic reactions was observed with Abciximab treatment (see WARNINGS: Allergic Reactions).
In a study of readministration of Abciximab to patients (see PRECAUTIONS: Readministration) the overall rate of HACA positivity prior to the readministration was 6% and increased post-readministration to 27%. Among the 36 subjects receiving a fourth or greater Abciximab exposure, HACA positive assays were observed post-readministration in 16 subjects (44%).
There were no reports of serious allergic reactions or anaphylaxis (see WARNINGS: Allergic Reactions). HACA positive status was associated with an increased risk of thrombocytopenia (see PRECAUTIONS: Thrombocytopenia).
The data reflect the percentage of patients whose test results were considered positive for antibodies to Abciximab using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Abciximab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Abiciximab Postmarketing Experience in the drug label.
# Drug Interactions
Formal drug interaction studies with Abciximab have not been conducted. Abciximab has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina, myocardial infarction and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors, intravenous and oral nitrates, ticlopidine, and aspirin. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Animal reproduction studies have not been conducted with Abciximab. It is also not known whether Abciximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Abciximab should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abiciximab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abiciximab during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Abciximab is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been studied.
### Geriatic Use
Of the total number of 7860 patients in the four Phase 3 trials, 2933 (37%) were 65 and over, while 653 (8%) were 75 and over. No overall differences in safety or efficacy were observed between patients of age 65 to less than 75 as compared to younger patients. The clinical experience is not adequate to determine whether patients of age 75 or greater respond differently than younger patients.
### Gender
There is no FDA guidance on the use of Abiciximab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abiciximab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Abiciximab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Abiciximab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Abiciximab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Abiciximab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin as described in clinical studies.
In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting.
In the event of serious bleeding that cannot be controlled by compression, Abciximab and heparin should be discontinued immediately.
The recommended dosage of Abciximab in adults is a 0.25 mg/kg intravenous bolus administered 10-60 minutes before the start of PCI, followed by a continuous intravenous infusion of 0.125 μg/kg/min (to a maximum of 10 μg/min) for 12 hours.
Patients with unstable angina not responding to conventional medical therapy and who are planned to undergo PCI within 24 hours may be treated with an Abciximab 0.25 mg/kg intravenous bolus followed by an 18- to 24-hour intravenous infusion of 10 μg/min, concluding one hour after the PCI.
### Instructions for Administration
Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of Abciximab containing visibly opaque particles should NOT be used.
Hypersensitivity reactions should be anticipated whenever protein solutions such as Abciximab are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given (see WARNINGS: Allergic Reactions).
As with all parenteral drug products, aseptic procedures should be used during the administration of Abciximab.
Withdraw the necessary amount of Abciximab for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent).
Withdraw the necessary amount of Abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent) or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter (Abbott #4524 or equivalent). Discard the unused portion at the end of the infusion.
No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications.
No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.
### Monitoring
- Vascular puncture sites should be documented and monitored.
- Any hematoma should be measured and monitored for enlargement.
- Platelet counts should be monitored prior to, during, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal.
- If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated.
# IV Compatibility
- No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications.
- No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.
# Overdosage
There has been no experience of overdosage in human clinical trials
# Pharmacology
There is limited information regarding Abiciximab Pharmacology in the drug label.
## Mechanism of Action
The mechanism of action is thought to involve steric hindrance and/or conformational effects to block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa.
## Structure
Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (αvβ3) receptor found on platelets and vessel wall endothelial and smooth muscle cells.
The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain and column chromatography.
ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added.
## Pharmacodynamics
Intravenous administration in humans of single bolus doses of Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately five minutes.
Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade GPIIb/IIIa receptor blockade (≥ 80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 5 μM or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Similar results were obtained when a weight-adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients weighing up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. The onset of Abciximab-mediated platelet inhibition following a 0.25 mg/kg bolus and 0.125 μg/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of baseline in 8 of 10 patients at 10 minutes after treatment initiation.
Low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following cessation of the infusion. After discontinuation of Abciximab infusion, platelet function returns gradually to normal. Bleeding time returned to ≤ 12 minutes within 12 hours following the end of infusion in 15 of 20 patients (75%), and within 24 hours in 18 of 20 patients (90%). Ex vivo platelet aggregation in response to 5 μM ADP returned to ≥ 50% of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and within 48 hours in 23 of 32 patients (72%). In response to 20 μM ADP, ex vivo platelet aggregation returned to ≥ 50% of baseline within 24 hours in 20 of 32 patients (62%) and within 48 hours in 28 of 32 patients (88%).
## Pharmacokinetics
Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. Platelet function generally recovers over the course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of Abciximab followed by continuous infusion of 10 μg/min (or a weight-adjusted infusion of 0.125 μg/kg/min to a maximum of 10 μg/min) produces approximately constant free plasma concentrations throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate.
## Nonclinical Toxicology
In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on fertility in male or female animals.
# Clinical Studies
Abciximab has been studied in four Phase 3 clinical trials, all of which evaluated the effect of Abciximab in patients undergoing percutaneous coronary intervention (PCI): in patients at high risk for abrupt closure of the treated coronary vessel (EPIC), in a broader group of patients (EPILOG), in unstable angina patients not responding to conventional medical therapy (CAPTURE), and in patients suitable for either conventional angioplasty/atherectomy or primary stent implantation (EPILOG Stent; EPISTENT). Percutaneous intervention included balloon angioplasty, atherectomy, or stent placement. All trials involved the use of various, concomitant heparin dose regimens and, unless contraindicated, aspirin (325 mg) was administered orally two hours prior to the planned procedure and then once daily.
EPIC was a multicenter, double-blind, placebo-controlled trial of Abciximab in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) who were at high risk for abrupt closure of the treated coronary vessel (7). Patients were allocated to treatment with: 1) Abciximab bolus plus infusion for 12 hours; 2) Abciximab bolus plus placebo infusion, or; 3) placebo bolus plus infusion. All patients received concomitant heparin (10,000 to 12,000 U bolus followed by an infusion for 12 hours).
The primary endpoint was the composite of death, myocardial infarction (MI), or urgent intervention for recurrent ischemia within 30 days of randomization. The primary endpoint event rates in the Abciximab bolus plus infusion group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days (7), 6 months (8), and three years (9).
EPILOG was a randomized, double-blind, multicenter, placebo-controlled trial which evaluated Abciximab in a broad population of patients undergoing PCI (excluding patients with myocardial infarction and unstable angina meeting the EPIC high risk criteria) (10). Study procedures emphasized discontinuation of heparin after the procedure with early femoral arterial sheath removal and careful access site management (see PRECAUTIONS). EPILOG was a three-arm trial comparing Abciximab plus standard-dose heparin, Abciximab plus low-dose heparin, and placebo plus standard-dose heparin. Abciximab and heparin infusions were weight-adjusted in all arms. The Abciximab bolus plus infusion regimen was: 0.25 mg/kg bolus followed by a 0.125 μg/kg/min infusion (to a maximum of 10 μg/min) for 12 hours. The heparin regimen was either a standard-dose regimen (initial 100 U/kg bolus, target ACT ≥ 300 seconds) or a low-dose regimen (initial 70 U/kg bolus, target ACT ≥ 200 seconds).
The primary endpoint of the EPILOG trial was the composite of death or MI occurring within 30 days of PCI. The composite of death, MI, or urgent intervention was an important secondary endpoint. The endpoint events in the Abciximab treatment group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days and six months (10) and one year (11). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 1.
At the six-month follow up visit, the event rate for death, MI, or repeat (urgent or non-urgent) intervention remained lower in the Abciximab treatment arms (22.3% and 22.8%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (25.8%) and the event rate for death, MI, or urgent intervention was substantially lower in the Abciximab treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%). The treatment associated effects continued to persist at the one-year follow up visit. The proportionate reductions in endpoint event rates were similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy, or stent placement). Risk assessment using the American College of Cardiology/American Heart Association clinical/morphological criteria had large inter-observer variability. Consequently, a low risk subgroup could not be reproducibly identified in which to evaluate efficacy.
The EPISTENT trial was a randomized, multicenter trial evaluating three different treatment strategies in patients undergoing PCI: conventional PTCA with Abciximab plus low-dose heparin, primary intracoronary stent implantation with Abciximab plus low-dose heparin, and primary intracoronary stent implantation with placebo plus standard-dose heparin (12). The heparin dose was weight-adjusted in all arms. The JJIS Palmaz-Schatz stent was used in over 90% of the patients receiving stents. The two stent arms were blinded with respect to study agent (Abciximab or placebo) and heparin dose; the PCI arm with Abciximab was open-label. The Abciximab bolus plus infusion regimen was the same as that used in the EPILOG trial. The standard-dose and low-dose heparin regimens were the same as those used in the EPILOG trial. All patients were to receive aspirin; ticlopidine, if given, was to be started prior to study agent. Patient and access site management guidelines were the same as those for EPILOG, including a strong recommendation for early sheath removal.
The results demonstrated benefit in both Abciximab arms (i.e., with and without stents) compared with stenting alone on the composite of death, MI, or urgent intervention (repeat PCI or CABG) within 30 days of PCI (12). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 2.
This benefit was maintained at 6 months: 12.1% of patients in the placebo/stent group experienced death, MI, or urgent revascularization compared with 6.4% of patients in the Abciximab/stent group (p<0.001 vs placebo/stent) and 9.2% in the Abciximab/PTCA group (p=0.051 vs placebo/stent). At 6 months, a reduction in the composite of death, MI, or all repeat (urgent or non-urgent) intervention was observed in the Abciximab/stent group compared with the placebo/stent group (15.4% vs 20.4%, p=0.006); the rate of this composite endpoint was similar in the Abciximab/PTCA and placebo/stent groups (22.4% vs 20.4%, p=0.467). (13)
CAPTURE was a randomized, double-blind, multicenter, placebo-controlled trial of the use of Abciximab in unstable angina patients not responding to conventional medical therapy for whom PCI was planned, but not immediately performed (14). The CAPTURE trial involved the administration of placebo or Abciximab starting 18 to 24 hours prior to PCI and continuing until one hour after completion of the intervention.
Patients were assessed as having unstable angina not responding to conventional medical therapy if they had at least one episode of myocardial ischemia despite bed rest and at least two hours of therapy with intravenous heparin and oral or intravenous nitrates. These patients were enrolled into the CAPTURE trial, if during a screening angiogram, they were determined to have a coronary lesion amenable to PCI. Patients received a bolus dose and intravenous infusion of placebo or Abciximab for 18 to 24 hours. At the end of the infusion period, the intervention was performed. The Abciximab or placebo infusion was discontinued one hour following the intervention. Patients were treated with intravenous heparin and oral or intravenous nitrates throughout the 18- to 24-hour Abciximab infusion period prior to the PCI.
The Abciximab dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial incorporated weight adjustment of the standard heparin dose only during the performance of the intervention, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours. The primary endpoint of the CAPTURE trial was the occurrence of any of the following events within 30 days of PCI: death, MI, or urgent intervention. The 30-day (Kaplan-Meier) primary endpoint event rates are shown in Table 3.
The 30-day results are consistent with the results of the other three trials, with the greatest effects on the myocardial infarction and urgent intervention components of the composite endpoint. As secondary endpoints, the components of the composite endpoint were analyzed separately for the period prior to the PCI and the period from the beginning of the intervention through Day 30. The greatest difference in MI occurred in the post-intervention period: the rates of MI were lower in the Abciximab group compared with placebo (Abciximab 3.6%, placebo 6.1%). There was also a reduction in MI occurring prior to the PCI (Abciximab 0.6%, placebo 2.0%). An Abciximab-associated reduction in the incidence of urgent intervention occurred in the post-intervention period. No effect on mortality was observed in either period. At six months of follow up, the composite endpoint of death, MI, or all repeat intervention (urgent or non-urgent) was not different between the Abciximab and placebo groups (Abciximab 31.0%, placebo 30.8%, p=0.77).
Mortality was uncommon in all four trials. Similar mortality rates were observed in all arms within each trial. Patient follow-up through one year of the EPISTENT trial suggested decreased mortality among patients treated with Abciximab and stent placement compared to patients treated with stent alone (8/794 vs. 19/809, p=0.037). Data from earlier studies with balloon angioplasty were not suggestive of the same benefit. In all four trials, the rates of acute MI were significantly lower in the groups treated with Abciximab. Most of the Abciximab treatment effect was seen in reduction in the rate of acute non-Q-wave MI. Urgent intervention rates were also lower in Abciximab-treated groups in these trials.
### Anticoagulation
Weight-adjusted low dose heparin, weight-adjusted Abciximab, careful vascular access site management and discontinuation of heparin after the procedure with early femoral arterial sheath removal were used.
The initial heparin bolus was based upon the results of the baseline ACT, according to the following regimen:
ACT < 150 seconds: administer 70 U/kg heparin
ACT 150 - 199 seconds: administer 50 U/kg heparin
ACT ≥ 200 seconds: administer no heparin
Additional 20 U/kg heparin boluses were given to achieve and maintain an ACT of ≥ 200 seconds during the procedure.
Discontinuation of heparin immediately after the procedure and removal of the arterial sheath within six hours were strongly recommended in the trials. If prolonged heparin therapy or delayed sheath removal was clinically indicated, heparin was adjusted to keep the APTT at a target of 60 to 85 seconds (EPILOG) or 55 to 75 seconds (EPISTENT).
Anticoagulation was initiated prior to the administration of Abciximab. Anticoagulation was initiated with an intravenous heparin infusion to achieve a target APTT of 60 to 85 seconds. The heparin infusion was not uniformly weight adjusted in this trial. The heparin infusion was maintained during the Abciximab infusion and was adjusted to achieve an ACT of 300 seconds or an APTT of 70 seconds during the PCI. Following the intervention, heparin management was as outlined above for the EPILOG trial.
# How Supplied
Abciximab (ReoPro®) 2 mg/mL is supplied in 5 mL vials containing 10 mg (NDC 0002-7140-01).
## Storage
Vials should be stored at 2 to 8 °C (36 to 46 °F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Abiciximab Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Abiciximab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Abiciximab Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Abiciximab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Abiciximab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Abiciximab is a Platelet aggregation inhibitor that is FDA approved for the {{{indicationType}}} of prevention of cardiac ischemic complications in patients undergoing percutaneous coronary intervention and in patients with unstable angina not responding to conventional medical therapy when percutaneous coronary intervention is planned within 24 hours. Common adverse reactions include Chest pain , Hypotension ,Injection site pain ,Abdominal pain , Nausea, Vomiting Bleeding
Backache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- initial dosage: 0.25 mg/kg IV bolus (10-60 minutes before the start of PCI)
- maitaining dosage: 0.125 mg/kg/min IV for 12 hours (max 10 ug/min)
- Dosing Information
- initial dosage: 0.25 mg/kg IV (10-60 minutes before the start of PCI)
- maitaining dosage: 10 ug/min IV for 18- 24h (concluding one hour after the PCI)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)
- Class of Recommendation: Class IIa
- Level of Evidence: Level A
- Recommendation
- initial dosage: 0.25 mg/kg IV bolus (over 5 minutes)
- maitaing dosage: 10 ug/min IV (continued for 12 hours unless complications developed)
### Non–Guideline-Supported Use
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h [1]
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h [2]
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h [3]
- Dosing information
- initial dosage: 0.25 mg/kg IV bolus
- maitaing dosage: 10 ug/min IV for 12h [4]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Abiciximab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Non–Guideline-Supported Use
- Dosing information
- loading dose: 0.25 mg/kg IV
- follow-up: 0.125 mg/min IV for 12h [5]
# Contraindications
Because Abciximab may increase the risk of bleeding, Abciximab is contraindicated in the following clinical situations:
- Active internal bleeding
- Recent (within six weeks) gastrointestinal (GI) or genitourinary (GU) bleeding of clinical significance.
- History of cerebrovascular accident (CVA) within two years, or CVA with a significant residual neurological deficit
- Bleeding diathesis
- Administration of oral anticoagulants within seven days unless prothrombin time is <1.2 times control
- Thrombocytopenia (<100,000 cells/mL)
- Recent (within six weeks) major surgery or trauma
- Intracranial neoplasm, arteriovenous malformation, or aneurysm
- Severe uncontrolled hypertension
- Presumed or documented history of vasculitis
- Use of intravenous dextran before PCI, or intent to use it during an intervention
Abciximab is also contraindicated in patients with known hypersensitivity to any component of this product or to murine proteins.
# Warnings
Abciximab has the potential to increase the risk of bleeding events, rarely including those with a fatal outcome, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants, or thrombolytics (see ADVERSE REACTIONS: Bleeding).
The risk of major bleeds due to Abciximab therapy is increased in patients receiving thrombolytics and should be weighed against the anticipated benefits.
Should serious bleeding occur that is not controllable with pressure, the infusion of Abciximab and any concomitant heparin should be stopped.
Allergic reactions, some of which were anaphylaxis (sometimes fatal), have been reported rarely in patients treated with ReoPro. Patients with allergic reactions should receive appropriate treatment. Treatment of anaphylaxis should include immediate discontinuation of ReoPro administration and initiation of resuscitative measures.
## Precautions
To minimize the risk of bleeding with Abciximab, it is important to use a low-dose, weight-adjusted heparin regimen, a weight-adjusted Abciximab bolus and infusion, strict anticoagulation guidelines, careful vascular access site management, discontinuation of heparin after the procedure and early femoral arterial sheath removal.
Therapy with Abciximab requires careful attention to all potential bleeding sites including catheter insertion sites, arterial and venous puncture sites, cutdown sites, needle puncture sites, and gastrointestinal, genitourinary, pulmonary (alveolar), and retroperitoneal sites.
Arterial and venous punctures, intramuscular injections, and use of urinary catheters, nasotracheal intubation, nasogastric tubes and automatic blood pressure cuffs should be minimized. When obtaining intravenous access, non-compressible sites (e.g., subclavian or jugular veins) should be avoided. Saline or heparin locks should be considered for blood drawing. Vascular puncture sites should be documented and monitored. Gentle care should be provided when removing dressings.
Arterial access site care is important to prevent bleeding. Care should be taken when attempting vascular access that only the anterior wall of the femoral artery is punctured, avoiding a Seldinger (through and through) technique for obtaining sheath access. Femoral vein sheath placement should be avoided unless needed. While the vascular sheath is in place, patients should be maintained on complete bed rest with the head of the bed ≤ 30° and the affected limb restrained in a straight position. Patients may be medicated for back/groin pain as necessary.
Discontinuation of heparin immediately upon completion of the procedure and removal of the arterial sheath within six hours is strongly recommended if APTT ≤ 50 sec or ACT≤ 175 sec (see PRECAUTIONS: Laboratory Tests). In all circumstances, heparin should be discontinued at least two hours prior to arterial sheath removal.
Following sheath removal, pressure should be applied to the femoral artery for at least 30 minutes using either manual compression or a mechanical device for hemostasis. A pressure dressing should be applied following hemostasis. The patient should be maintained on bed rest for six to eight hours following sheath removal or discontinuation of Abciximab, or four hours following discontinuation of heparin, whichever is later. The pressure dressing should be removed prior to ambulation. The sheath insertion site and distal pulses of affected leg(s) should be frequently checked while the femoral artery sheath is in place and for six hours after femoral artery sheath removal. Any hematoma should be measured and monitored for enlargement.
The following conditions have been associated with an increased risk of bleeding and may be additive with the effect of Abciximab in the angioplasty setting: PCI within 12 hours of the onset of symptoms for acute myocardial infarction, prolonged PCI (lasting more than 70 minutes) and failed PCI.
In the EPIC, EPILOG, CAPTURE, and EPISTENT trials, Abciximab was used concomitantly with heparin and aspirin.
For details of the anticoagulation algorithms used in these clinical trials, see CLINICAL STUDIES: Anticoagulation. Because Abciximab inhibits platelet aggregation, caution should be employed when it is used with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, non-steroidal anti-inflammatory drugs, dipyridamole, and ticlopidine.
In the EPIC trial, there was limited experience with the administration of Abciximab with low molecular weight dextran. Low molecular weight dextran was usually given for the deployment of a coronary stent, for which oral anticoagulants were also given. In the 11 patients who received low molecular weight dextran with Abciximab, five had major bleeding events and four had minor bleeding events. None of the five placebo patients treated with low molecular weight dextran had a major or minor bleeding event (see CONTRAINDICATIONS).
Because of observed synergistic effects on bleeding, Abciximab therapy should be used judiciously in patients who have received systemic thrombolytic therapy. The GUSTO V trial randomized patients with acute myocardial infarction to treatment with combined Abciximab and half-dose Reteplase, or full-dose Reteplase alone (15). In this trial, the incidence of moderate or severe nonintracranial bleeding was increased in those patients receiving Abciximab and half-dose Reteplase versus those receiving Reteplase alone (4.6% versus 2.3%, respectively).
Thrombocytopenia, including severe thrombocytopenia, has been observed with Abciximab administration (see ADVERSE REACTIONS: Thrombocytopenia). Platelet counts should be monitored prior to, during, and after treatment with Abciximab. Acute decreases in platelet count should be differentiated between true thrombocytopenia and pseudothrombocytopenia (see PRECAUTIONS: Laboratory Tests). If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated.
In clinical trials, patients who developed thrombocytopenia were followed with daily platelet counts until their platelet count returned to normal. Heparin and aspirin were discontinued for platelet counts below 60,000 cells/μL and platelets were transfused for a platelet count below 50,000 cells/μL. Most cases of severe thrombocytopenia (< 50,000 cells/μL) occurred within the first 24 hours of Abciximab administration.
In a registry study of Abciximab readministration, a history of thrombocytopenia associated with prior use of Abciximab was predictive of an increased risk of recurrent thrombocytopenia (see ADVERSE REACTIONS: Thrombocytopenia). Readministration within 30 days was associated with an increased incidence and severity of thrombocytopenia, as was a positive human anti-chimeric antibody (HACA) test at baseline, compared to the rates seen in studies with first administration.
Restoration of Platelet Function- In the event of serious uncontrolled bleeding or the need for emergency surgery, Abciximab should be discontinued. If platelet function does not return to normal, it may be restored, at least in part, with platelet transfusions.
Before infusion of Abciximab, prothrombin time, ACT, APTT, and platelet count should be measured to identify pre-existing hemostatic abnormalities.
Based on an integrated analysis of data from all studies, the following guidelines may be utilized to minimize the risk for bleeding:
- When Abciximab is initiated 18 to 24 hours before PCI, the APTT should be maintained between 60 and 85 seconds during the Abciximab and heparin infusion period.
- During PCI the ACT should be maintained between 200 and 300 seconds.
- If anticoagulation is continued in these patients following PCI, the APTT should be maintained between 55 and 75 seconds.
- The APTT or ACT should be checked prior to arterial sheath removal. The sheath should not be removed unless APTT ≤ 50 seconds or ACT ≤ 175 seconds.
- Platelet counts should be monitored prior to treatment, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal.
- To exclude pseudothrombocytopenia, a laboratory artifact due to in vitro anticoagulant interaction, blood samples should be drawn in three separate tubes containing ethylenediaminetetraacetic acid (EDTA), citrate and heparin, respectively. A low platelet count in EDTA but not in heparin and/or citrate is supportive of a diagnosis of pseudothrombocytopenia.
Administration of Abciximab may result in the formation of HACA that could potentially cause allergic or hypersensitivity reactions (including anaphylaxis), thrombocytopenia or diminished benefit upon readministration of Abciximab (see WARNINGS: Allergic Reactions; see ADVERSE REACTIONS: Immunogenicity).
Readministration of Abciximab to patients undergoing PCI was assessed in a registry that included 1342 treatments in 1286 patients. Most patients were receiving their second
Abciximab exposure; 15% were receiving the third or subsequent exposure. The overall rate of HACA positivity prior to the readministration was 6% and increased to 27% post-readministration. There were no reports of serious allergic reactions or anaphylaxis (see WARNINGS: Allergic Reactions). Thrombocytopenia was observed at higher rates in the readministration study than in the phase 3 studies of first-time administration (see PRECAUTIONS: Thrombocytopenia and Adverse Reactions: Thrombocytopenia), suggesting that readministration may be associated with an increased incidence and severity of thrombocytopenia.
# Adverse Reactions
## Clinical Trials Experience
### Bleeding
Abciximab has the potential to increase the risk of bleeding, particularly in the presence of anticoagulation, e.g., from heparin, other anticoagulants or thrombolytics. Bleeding in the Phase 3 trials was classified as major, minor or insignificant by the criteria of the Thrombolysis in Myocardial Infarction study group (16). Major bleeding events were defined as either an intracranial hemorrhage or a decrease in hemoglobin greater than 5 g/dL. Minor bleeding events included spontaneous gross hematuria, spontaneous hematemesis, observed blood loss with a hemoglobin decrease of more than 3 g/dL, or a decrease in hemoglobin of at least 4 g/dL without an identified bleeding site. Insignificant bleeding events were defined as a decrease in hemoglobin of less than 3 g/dL or a decrease in hemoglobin between 3-4 g/dL without observed bleeding. In patients who received transfusions, the number of units of blood lost was estimated through an adaptation of the method of Landefeld, et al. (17).
In the EPIC trial, in which a non-weight-adjusted, longer-duration heparin dose regimen was used, the most common complication during Abciximab therapy was bleeding during the first 36 hours. The incidences of major bleeding, minor bleeding and transfusion of blood products were significantly increased. Major bleeding occurred in 10.6% of patients in the Abciximab bolus plus infusion arm compared with 3.3% of patients in the placebo arm. Minor bleeding was seen in 16.8% of Abciximab bolus plus infusion patients and 9.2% of placebo patients (7). Approximately 70% of Abciximab-treated patients with major bleeding had bleeding at the arterial access site in the groin. Abciximab-treated patients also had a higher incidence of major bleeding events from gastrointestinal, genitourinary, retroperitoneal, and other sites.
Bleeding rates were reduced in the CAPTURE trial, and further reduced in the EPILOG and EPISTENT trials by use of modified dosing regimens and specific patient management techniques. In EPILOG and EPISTENT, using the heparin and Abciximab dosing, sheath removal and arterial access site guidelines described under PRECAUTIONS, the incidence of major bleeding in patients treated with Abciximab and low-dose, weight-adjusted heparin was not significantly different from that in patients receiving placebo.
Subgroup analyses in the EPIC and CAPTURE trials showed that non-CABG major bleeding was more common in Abciximab patients weighing ≤ 75 kg. In the EPILOG and EPISTENT trials, which used weight-adjusted heparin dosing, the non-CABG major bleeding rates for Abciximab-treated patients did not differ substantially by weight subgroup.
Although data are limited, Abciximab treatment was not associated with excess major bleeding in patients who underwent CABG surgery. (The range among all treatment arms was 3-5% in EPIC, and 1-2% in the CAPTURE, EPILOG, and EPISTENT trials.) Some patients with prolonged bleeding times received platelet transfusions to correct the bleeding time prior to surgery. (see PRECAUTIONS: Restoration of Platelet Function.)
The rates of major bleeding, minor bleeding and bleeding events requiring transfusions in the CAPTURE, EPILOG, and EPISTENT trials are shown in Table 4. The rates of insignificant bleeding events are not included in Table 4.
Cases of fatal bleeding have been reported rarely during post-marketing use of Abciximab (see WARNINGS: Bleeding Events).
Pulmonary alveolar hemorrhage has been rarely reported during use of Abciximab. This can present with any or all of the following in close association with ReoPro administration: hypoxemia, alveolar infiltrates on chest x-ray, hemoptysis, or an unexplained drop in hemoglobin.
### Intracranial Hemorrhage and Stroke
The total incidence of intracranial hemorrhage and non-hemorrhagic stroke across all four trials was not significantly different, 9/3023 for placebo patients and 15/4680 for Abciximab-treated patients. The incidence of intracranial hemorrhage was 3/3023 for placebo patients and 7/4680 for Abciximab patients.
### Thrombocytopenia
In the clinical trials, patients treated with Abciximab were more likely than patients treated with placebo to experience decreases in platelet counts.
Among patients in the EPILOG and EPISTENT trials who were treated with Abciximab plus low-dose heparin, the proportion of patients with any thrombocytopenia (platelets less than 100,000 cells/μL) ranged from 2.5 to 3.0%. The incidence of severe thrombocytopenia (platelets less than 50,000 cells/μL) ranged from 0.4 to 1.0% and platelet transfusions were required in 0.9 to 1.1%, respectively. Modestly lower rates were observed among patients treated with placebo plus standard-dose heparin. Overall higher rates were observed among patients in the EPIC and CAPTURE trials treated with Abciximab plus longer duration heparin: 2.6 to 5.2% were found to have any thrombocytopenia, 0.9 to 1.7% had severe thrombocytopenia, and 2.1 to 5.5% required platelet transfusion, respectively.
In a readministration registry study of patients receiving a second or subsequent exposure to Abciximab (see PRECAUTIONS: Readministration) the incidence of any degree of thrombocytopenia was 5%, with an incidence of profound thrombocytopenia of 2% (<20,000 cell/μL). Factors associated with an increased risk of thrombocytopenia were a history of thrombocytopenia on previous Abciximab exposure, readministration within 30 days, and a positive HACA assay prior to the readministration.
Among 14 patients who had thrombocytopenia associated with a prior exposure to Abciximab, 7 (50%) had recurrent thrombocytopenia. In 130 patients with a readministration interval of 30 days or less, 25 (19%) developed thrombocytopenia. Severe thrombocytopenia occurred in 19 of these patients. Among the 71 patients who had a positive HACA assay at baseline, 11 (15%) developed thrombocytopenia, 7 of which were severe.
### Allergic Reactions
There have been rare reports of allergic reactions, some of which were anaphylaxis (see WARNINGS: Allergic Reactions).
### Other Adverse Reactions
Table 5 shows adverse events other than bleeding and thrombocytopenia from the combined EPIC, EPILOG and CAPTURE trials which occurred in patients in the bolus plus infusion arm at an incidence of more than 0.5% higher than in those treated with placebo.
The following additional adverse events from the EPIC, EPILOG and CAPTURE trials were reported by investigators for patients treated with a bolus plus infusion of Abciximab at incidences which were less than 0.5% higher than for patients in the placebo arm.
Cardiovascular System: ventricular tachycardia (1.4%), pseudoaneurysm (0.8%), palpitation (0.5%), arteriovenous fistula (0.4%), incomplete AV block (0.3%), nodal arrhythmia (0.2%), complete AV block (0.1%), embolism (limb)(0.1%); thrombophlebitis (0.1%);
Gastrointestinal System: dyspepsia (2.1%), diarrhea (1.1%), ileus (0.1%), gastroesophogeal reflux (0.1%);
Hemic and Lymphatic System: anemia (1.3%), leukocytosis (0.5%), petechiae (0.2%);
Nervous System: dizziness (2.9%), anxiety (1.7%), abnormal thinking (1.3%), agitation (0.7%), hypesthesia (0.6%), confusion (0.5%) muscle contractions (0.4%), coma (0.2%), hypertonia (0.2%), diplopia (0.1%);
Respiratory System: pneumonia (0.4%), rales (0.4%), pleural effusion (0.3%), bronchitis (0.3%) bronchospasm (0.3%), pleurisy (0.2%), pulmonary embolism (0.2%), rhonchi (0.1%);
Musculoskeletal System: myalgia (0.2%);
Urogenital System: urinary retention (0.7%), dysuria (0.4%), abnormal renal function (0.4%), frequent micturition (0.1%), cystalgia (0.1%), urinary incontinence (0.1%), prostatitis (0.1%);
Miscellaneous: pain (5.4%), sweating increased (1.0%), asthenia (0.7%), incisional pain (0.6%), pruritus (0.5%), abnormal vision (0.3%), edema (0.3%), wound (0.2%), abscess (0.2%), cellulitis (0.2%), peripheral coldness (0.2%), injection site pain (0.1%), dry mouth (0.1%), pallor (0.1%), diabetes mellitus (0.1%), hyperkalemia (0.1%), enlarged abdomen (0.1%), bullous eruption (0.1%), inflammation (0.1%), drug toxicity (0.1%).
### Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. In the EPIC, EPILOG, and CAPTURE trials, positive HACA responses occurred in approximately 5.8% of these patients receiving a first exposure to Abciximab. No increase in hypersensitivity or allergic reactions was observed with Abciximab treatment (see WARNINGS: Allergic Reactions).
In a study of readministration of Abciximab to patients (see PRECAUTIONS: Readministration) the overall rate of HACA positivity prior to the readministration was 6% and increased post-readministration to 27%. Among the 36 subjects receiving a fourth or greater Abciximab exposure, HACA positive assays were observed post-readministration in 16 subjects (44%).
There were no reports of serious allergic reactions or anaphylaxis (see WARNINGS: Allergic Reactions). HACA positive status was associated with an increased risk of thrombocytopenia (see PRECAUTIONS: Thrombocytopenia).
The data reflect the percentage of patients whose test results were considered positive for antibodies to Abciximab using an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Abciximab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Abiciximab Postmarketing Experience in the drug label.
# Drug Interactions
Formal drug interaction studies with Abciximab have not been conducted. Abciximab has been administered to patients with ischemic heart disease treated concomitantly with a broad range of medications used in the treatment of angina, myocardial infarction and hypertension. These medications have included heparin, warfarin, beta-adrenergic receptor blockers, calcium channel antagonists, angiotensin converting enzyme inhibitors, intravenous and oral nitrates, ticlopidine, and aspirin. Heparin, other anticoagulants, thrombolytics, and antiplatelet agents are associated with an increase in bleeding. Patients with HACA titers may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Animal reproduction studies have not been conducted with Abciximab. It is also not known whether Abciximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Abciximab should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS): C
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abiciximab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Abiciximab during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, caution should be exercised when Abciximab is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been studied.
### Geriatic Use
Of the total number of 7860 patients in the four Phase 3 trials, 2933 (37%) were 65 and over, while 653 (8%) were 75 and over. No overall differences in safety or efficacy were observed between patients of age 65 to less than 75 as compared to younger patients. The clinical experience is not adequate to determine whether patients of age 75 or greater respond differently than younger patients.
### Gender
There is no FDA guidance on the use of Abiciximab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Abiciximab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Abiciximab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Abiciximab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Abiciximab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Abiciximab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
The safety and efficacy of Abciximab have only been investigated with concomitant administration of heparin and aspirin as described in clinical studies.
In patients with failed PCIs, the continuous infusion of Abciximab should be stopped because there is no evidence for Abciximab efficacy in that setting.
In the event of serious bleeding that cannot be controlled by compression, Abciximab and heparin should be discontinued immediately.
The recommended dosage of Abciximab in adults is a 0.25 mg/kg intravenous bolus administered 10-60 minutes before the start of PCI, followed by a continuous intravenous infusion of 0.125 μg/kg/min (to a maximum of 10 μg/min) for 12 hours.
Patients with unstable angina not responding to conventional medical therapy and who are planned to undergo PCI within 24 hours may be treated with an Abciximab 0.25 mg/kg intravenous bolus followed by an 18- to 24-hour intravenous infusion of 10 μg/min, concluding one hour after the PCI.
### Instructions for Administration
Parenteral drug products should be inspected visually for particulate matter prior to administration. Preparations of Abciximab containing visibly opaque particles should NOT be used.
Hypersensitivity reactions should be anticipated whenever protein solutions such as Abciximab are administered. Epinephrine, dopamine, theophylline, antihistamines and corticosteroids should be available for immediate use. If symptoms of an allergic reaction or anaphylaxis appear, the infusion should be stopped and appropriate treatment given (see WARNINGS: Allergic Reactions).
As with all parenteral drug products, aseptic procedures should be used during the administration of Abciximab.
Withdraw the necessary amount of Abciximab for bolus injection into a syringe. Filter the bolus injection using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent).
Withdraw the necessary amount of Abciximab for the continuous infusion into a syringe. Inject into an appropriate container of sterile 0.9% saline or 5% dextrose and infuse at the calculated rate via a continuous infusion pump. The continuous infusion should be filtered either upon admixture using a sterile, non-pyrogenic, low protein-binding 0.2 or 5 μm syringe filter (Millipore SLGV025LS or SLSV025LS or equivalent) or upon administration using an in-line, sterile, non-pyrogenic, low protein-binding 0.2 or 0.22 μm filter (Abbott #4524 or equivalent). Discard the unused portion at the end of the infusion.
No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications.
No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.
### Monitoring
- Vascular puncture sites should be documented and monitored.
- Any hematoma should be measured and monitored for enlargement.
- Platelet counts should be monitored prior to, during, two to four hours following the bolus dose of Abciximab and at 24 hours or prior to discharge, whichever is first. If a patient experiences an acute platelet decrease (e.g., a platelet decrease to less than 100,000 cells/μL and a decrease of at least 25% from pre-treatment value), additional platelet counts should be determined. Platelet monitoring should continue until platelet counts return to normal.
- If true thrombocytopenia is verified, Abciximab should be immediately discontinued and the condition appropriately monitored and treated.
# IV Compatibility
- No incompatibilities have been shown with intravenous infusion fluids or commonly used cardiovascular drugs. Nevertheless, Abciximab should be administered in a separate intravenous line whenever possible and not mixed with other medications.
- No incompatibilities have been observed with glass bottles or polyvinyl chloride bags and administration sets.
# Overdosage
There has been no experience of overdosage in human clinical trials
# Pharmacology
There is limited information regarding Abiciximab Pharmacology in the drug label.
## Mechanism of Action
The mechanism of action is thought to involve steric hindrance and/or conformational effects to block access of large molecules to the receptor rather than direct interaction with the RGD (arginine-glycine-aspartic acid) binding site of GPIIb/IIIa.
## Structure
Abciximab, ReoPro®, is the Fab fragment of the chimeric human-murine monoclonal antibody 7E3. Abciximab binds to the glycoprotein (GP) IIb/IIIa receptor of human platelets and inhibits platelet aggregation. Abciximab also binds to the vitronectin (αvβ3) receptor found on platelets and vessel wall endothelial and smooth muscle cells.
The chimeric 7E3 antibody is produced by continuous perfusion in mammalian cell culture. The 47,615 dalton Fab fragment is purified from cell culture supernatant by a series of steps involving specific viral inactivation and removal procedures, digestion with papain and column chromatography.
ReoPro® is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use. Each single use vial contains 2 mg/mL of Abciximab in a buffered solution (pH 7.2) of 0.01 M sodium phosphate, 0.15 M sodium chloride and 0.001% polysorbate 80 in Water for Injection. No preservatives are added.
## Pharmacodynamics
Intravenous administration in humans of single bolus doses of Abciximab from 0.15 mg/kg to 0.30 mg/kg produced rapid dose-dependent inhibition of platelet function as measured by ex vivo platelet aggregation in response to adenosine diphosphate (ADP) or by prolongation of bleeding time. At the two highest doses (0.25 and 0.30 mg/kg) at two hours post injection (the first time point evaluated), over 80% of the GPIIb/IIIa receptors were blocked and platelet aggregation in response to 20 μM ADP was almost abolished. The median bleeding time increased to over 30 minutes at both doses compared with a baseline value of approximately five minutes.
Intravenous administration in humans of a single bolus dose of 0.25 mg/kg followed by a continuous infusion of 10 μg/min for periods of 12 to 96 hours produced sustained high-grade GPIIb/IIIa receptor blockade (≥ 80%) and inhibition of platelet function (ex vivo platelet aggregation in response to 5 μM or 20 μM ADP less than 20% of baseline and bleeding time greater than 30 minutes) for the duration of the infusion in most patients. Similar results were obtained when a weight-adjusted infusion dose (0.125 μg/kg/min to a maximum of 10 μg/min) was used in patients weighing up to 80 kg. Results in patients who received the 0.25 mg/kg bolus followed by a 5 μg/min infusion for 24 hours showed a similar initial receptor blockade and inhibition of platelet aggregation, but the response was not maintained throughout the infusion period. The onset of Abciximab-mediated platelet inhibition following a 0.25 mg/kg bolus and 0.125 μg/kg/min infusion was rapid and platelet aggregation was reduced to less than 20% of baseline in 8 of 10 patients at 10 minutes after treatment initiation.
Low levels of GPIIb/IIIa receptor blockade are present for more than 10 days following cessation of the infusion. After discontinuation of Abciximab infusion, platelet function returns gradually to normal. Bleeding time returned to ≤ 12 minutes within 12 hours following the end of infusion in 15 of 20 patients (75%), and within 24 hours in 18 of 20 patients (90%). Ex vivo platelet aggregation in response to 5 μM ADP returned to ≥ 50% of baseline within 24 hours following the end of infusion in 11 of 32 patients (34%) and within 48 hours in 23 of 32 patients (72%). In response to 20 μM ADP, ex vivo platelet aggregation returned to ≥ 50% of baseline within 24 hours in 20 of 32 patients (62%) and within 48 hours in 28 of 32 patients (88%).
## Pharmacokinetics
Following intravenous bolus administration, free plasma concentrations of Abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of about 30 minutes, probably related to rapid binding to the platelet GPIIb/IIIa receptors. Platelet function generally recovers over the course of 48 hours (5,6), although Abciximab remains in the circulation for 15 days or more in a platelet-bound state. Intravenous administration of a 0.25 mg/kg bolus dose of Abciximab followed by continuous infusion of 10 μg/min (or a weight-adjusted infusion of 0.125 μg/kg/min to a maximum of 10 μg/min) produces approximately constant free plasma concentrations throughout the infusion. At the termination of the infusion period, free plasma concentrations fall rapidly for approximately six hours then decline at a slower rate.
## Nonclinical Toxicology
In vitro and in vivo mutagenicity studies have not demonstrated any mutagenic effect. Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on fertility in male or female animals.
# Clinical Studies
Abciximab has been studied in four Phase 3 clinical trials, all of which evaluated the effect of Abciximab in patients undergoing percutaneous coronary intervention (PCI): in patients at high risk for abrupt closure of the treated coronary vessel (EPIC), in a broader group of patients (EPILOG), in unstable angina patients not responding to conventional medical therapy (CAPTURE), and in patients suitable for either conventional angioplasty/atherectomy or primary stent implantation (EPILOG Stent; EPISTENT). Percutaneous intervention included balloon angioplasty, atherectomy, or stent placement. All trials involved the use of various, concomitant heparin dose regimens and, unless contraindicated, aspirin (325 mg) was administered orally two hours prior to the planned procedure and then once daily.
EPIC was a multicenter, double-blind, placebo-controlled trial of Abciximab in patients undergoing percutaneous transluminal coronary angioplasty or atherectomy (PTCA) who were at high risk for abrupt closure of the treated coronary vessel (7). Patients were allocated to treatment with: 1) Abciximab bolus plus infusion for 12 hours; 2) Abciximab bolus plus placebo infusion, or; 3) placebo bolus plus infusion. All patients received concomitant heparin (10,000 to 12,000 U bolus followed by an infusion for 12 hours).
The primary endpoint was the composite of death, myocardial infarction (MI), or urgent intervention for recurrent ischemia within 30 days of randomization. The primary endpoint event rates in the Abciximab bolus plus infusion group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days (7), 6 months (8), and three years (9).
EPILOG was a randomized, double-blind, multicenter, placebo-controlled trial which evaluated Abciximab in a broad population of patients undergoing PCI (excluding patients with myocardial infarction and unstable angina meeting the EPIC high risk criteria) (10). Study procedures emphasized discontinuation of heparin after the procedure with early femoral arterial sheath removal and careful access site management (see PRECAUTIONS). EPILOG was a three-arm trial comparing Abciximab plus standard-dose heparin, Abciximab plus low-dose heparin, and placebo plus standard-dose heparin. Abciximab and heparin infusions were weight-adjusted in all arms. The Abciximab bolus plus infusion regimen was: 0.25 mg/kg bolus followed by a 0.125 μg/kg/min infusion (to a maximum of 10 μg/min) for 12 hours. The heparin regimen was either a standard-dose regimen (initial 100 U/kg bolus, target ACT ≥ 300 seconds) or a low-dose regimen (initial 70 U/kg bolus, target ACT ≥ 200 seconds).
The primary endpoint of the EPILOG trial was the composite of death or MI occurring within 30 days of PCI. The composite of death, MI, or urgent intervention was an important secondary endpoint. The endpoint events in the Abciximab treatment group were reduced mostly in the first 48 hours and this benefit was sustained through 30 days and six months (10) and one year (11). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 1.
At the six-month follow up visit, the event rate for death, MI, or repeat (urgent or non-urgent) intervention remained lower in the Abciximab treatment arms (22.3% and 22.8%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (25.8%) and the event rate for death, MI, or urgent intervention was substantially lower in the Abciximab treatment arms (8.3% and 8.4%, respectively, for the standard- and low-dose heparin arms) than in the placebo arm (14.7%). The treatment associated effects continued to persist at the one-year follow up visit. The proportionate reductions in endpoint event rates were similar irrespective of the type of coronary intervention used (balloon angioplasty, atherectomy, or stent placement). Risk assessment using the American College of Cardiology/American Heart Association clinical/morphological criteria had large inter-observer variability. Consequently, a low risk subgroup could not be reproducibly identified in which to evaluate efficacy.
The EPISTENT trial was a randomized, multicenter trial evaluating three different treatment strategies in patients undergoing PCI: conventional PTCA with Abciximab plus low-dose heparin, primary intracoronary stent implantation with Abciximab plus low-dose heparin, and primary intracoronary stent implantation with placebo plus standard-dose heparin (12). The heparin dose was weight-adjusted in all arms. The JJIS Palmaz-Schatz stent was used in over 90% of the patients receiving stents. The two stent arms were blinded with respect to study agent (Abciximab or placebo) and heparin dose; the PCI arm with Abciximab was open-label. The Abciximab bolus plus infusion regimen was the same as that used in the EPILOG trial. The standard-dose and low-dose heparin regimens were the same as those used in the EPILOG trial. All patients were to receive aspirin; ticlopidine, if given, was to be started prior to study agent. Patient and access site management guidelines were the same as those for EPILOG, including a strong recommendation for early sheath removal.
The results demonstrated benefit in both Abciximab arms (i.e., with and without stents) compared with stenting alone on the composite of death, MI, or urgent intervention (repeat PCI or CABG) within 30 days of PCI (12). The (Kaplan-Meier) endpoint event rates at 30 days are shown in Table 2.
This benefit was maintained at 6 months: 12.1% of patients in the placebo/stent group experienced death, MI, or urgent revascularization compared with 6.4% of patients in the Abciximab/stent group (p<0.001 vs placebo/stent) and 9.2% in the Abciximab/PTCA group (p=0.051 vs placebo/stent). At 6 months, a reduction in the composite of death, MI, or all repeat (urgent or non-urgent) intervention was observed in the Abciximab/stent group compared with the placebo/stent group (15.4% vs 20.4%, p=0.006); the rate of this composite endpoint was similar in the Abciximab/PTCA and placebo/stent groups (22.4% vs 20.4%, p=0.467). (13)
CAPTURE was a randomized, double-blind, multicenter, placebo-controlled trial of the use of Abciximab in unstable angina patients not responding to conventional medical therapy for whom PCI was planned, but not immediately performed (14). The CAPTURE trial involved the administration of placebo or Abciximab starting 18 to 24 hours prior to PCI and continuing until one hour after completion of the intervention.
Patients were assessed as having unstable angina not responding to conventional medical therapy if they had at least one episode of myocardial ischemia despite bed rest and at least two hours of therapy with intravenous heparin and oral or intravenous nitrates. These patients were enrolled into the CAPTURE trial, if during a screening angiogram, they were determined to have a coronary lesion amenable to PCI. Patients received a bolus dose and intravenous infusion of placebo or Abciximab for 18 to 24 hours. At the end of the infusion period, the intervention was performed. The Abciximab or placebo infusion was discontinued one hour following the intervention. Patients were treated with intravenous heparin and oral or intravenous nitrates throughout the 18- to 24-hour Abciximab infusion period prior to the PCI.
The Abciximab dose was a 0.25 mg/kg bolus followed by a continuous infusion at a rate of 10 μg/min. The CAPTURE trial incorporated weight adjustment of the standard heparin dose only during the performance of the intervention, but did not investigate the effect of a lower heparin dose, and arterial sheaths were left in place for approximately 40 hours. The primary endpoint of the CAPTURE trial was the occurrence of any of the following events within 30 days of PCI: death, MI, or urgent intervention. The 30-day (Kaplan-Meier) primary endpoint event rates are shown in Table 3.
The 30-day results are consistent with the results of the other three trials, with the greatest effects on the myocardial infarction and urgent intervention components of the composite endpoint. As secondary endpoints, the components of the composite endpoint were analyzed separately for the period prior to the PCI and the period from the beginning of the intervention through Day 30. The greatest difference in MI occurred in the post-intervention period: the rates of MI were lower in the Abciximab group compared with placebo (Abciximab 3.6%, placebo 6.1%). There was also a reduction in MI occurring prior to the PCI (Abciximab 0.6%, placebo 2.0%). An Abciximab-associated reduction in the incidence of urgent intervention occurred in the post-intervention period. No effect on mortality was observed in either period. At six months of follow up, the composite endpoint of death, MI, or all repeat intervention (urgent or non-urgent) was not different between the Abciximab and placebo groups (Abciximab 31.0%, placebo 30.8%, p=0.77).
Mortality was uncommon in all four trials. Similar mortality rates were observed in all arms within each trial. Patient follow-up through one year of the EPISTENT trial suggested decreased mortality among patients treated with Abciximab and stent placement compared to patients treated with stent alone (8/794 vs. 19/809, p=0.037). Data from earlier studies with balloon angioplasty were not suggestive of the same benefit. In all four trials, the rates of acute MI were significantly lower in the groups treated with Abciximab. Most of the Abciximab treatment effect was seen in reduction in the rate of acute non-Q-wave MI. Urgent intervention rates were also lower in Abciximab-treated groups in these trials.
### Anticoagulation
Weight-adjusted low dose heparin, weight-adjusted Abciximab, careful vascular access site management and discontinuation of heparin after the procedure with early femoral arterial sheath removal were used.
The initial heparin bolus was based upon the results of the baseline ACT, according to the following regimen:
ACT < 150 seconds: administer 70 U/kg heparin
ACT 150 - 199 seconds: administer 50 U/kg heparin
ACT ≥ 200 seconds: administer no heparin
Additional 20 U/kg heparin boluses were given to achieve and maintain an ACT of ≥ 200 seconds during the procedure.
Discontinuation of heparin immediately after the procedure and removal of the arterial sheath within six hours were strongly recommended in the trials. If prolonged heparin therapy or delayed sheath removal was clinically indicated, heparin was adjusted to keep the APTT at a target of 60 to 85 seconds (EPILOG) or 55 to 75 seconds (EPISTENT).
Anticoagulation was initiated prior to the administration of Abciximab. Anticoagulation was initiated with an intravenous heparin infusion to achieve a target APTT of 60 to 85 seconds. The heparin infusion was not uniformly weight adjusted in this trial. The heparin infusion was maintained during the Abciximab infusion and was adjusted to achieve an ACT of 300 seconds or an APTT of 70 seconds during the PCI. Following the intervention, heparin management was as outlined above for the EPILOG trial.
# How Supplied
Abciximab (ReoPro®) 2 mg/mL is supplied in 5 mL vials containing 10 mg (NDC 0002-7140-01).
## Storage
Vials should be stored at 2 to 8 °C (36 to 46 °F). Do not freeze. Do not shake. Do not use beyond the expiration date. Discard any unused portion left in the vial
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Abiciximab Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Abiciximab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Abiciximab Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Abiciximab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Abiciximab | |
8b40e9256477ad39b97b7c716df70ebc95460aba | wikidoc | Tryptamine | Tryptamine
Tryptamine is a monoamine alkaloid found in plants and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived. Tryptamine is found in trace amounts in the brains of mammals and is believed to play a role as a neuromodulator or neurotransmitter.
Tryptamine is also the backbone for a group of compounds known collectively as tryptamines. This group includes many biologically active compounds, including neurotransmitters and hallucinogens.
The concentration of tryptamine in rat brains is about 3.5 pmol/g.
# Plants containing tryptamine
Many if not most plants contain small amounts of tryptamine which is an intermediate in one biosynthetic pathway to the plant hormone indole-3-acetic acid (heteroauxin). Higher concentrations can be found in many Acacia species.
Tryptamine acts as a natural pesticide in plants.
# Tryptamine derivatives
The most well-known tryptamines are serotonin, an important neurotransmitter, and melatonin, a hormone involved in regulating the sleep-wake cycle. Tryptamine alkaloids found in fungi, plants and animals are commonly used by humans for their psychotropic effects. Prominent examples include psilocybin (from "magic mushrooms") and DMT (from numerous plant sources, e.g. chacruna, often used in ayahuasca brews). Many synthetic tryptamines have also been made, including the migraine drug sumatriptan and its relatives. The tables below list some commonly encountered substituted tryptamines.
The tryptamine backbone can also be identified as part of the structure of some
more complex compounds, for example: LSD, ibogaine and yohimbine.
A thorough investigation of dozens of tryptamine compounds was published by Ann and Alexander Shulgin under the title TiHKAL.
The Abramovitch-Shapiro tryptamine synthesis is an organic reaction for the synthesis of tryptamines starting from a beta-Carboline | Tryptamine
Template:Chembox new
Tryptamine is a monoamine alkaloid found in plants and animals. It is based around the indole ring structure, and is chemically related to the amino acid tryptophan, from which its name is derived. Tryptamine is found in trace amounts in the brains of mammals and is believed to play a role as a neuromodulator or neurotransmitter.[1]
Tryptamine is also the backbone for a group of compounds known collectively as tryptamines. This group includes many biologically active compounds, including neurotransmitters and hallucinogens.
The concentration of tryptamine in rat brains is about 3.5 pmol/g.[2]
# Plants containing tryptamine
Many if not most plants contain small amounts of tryptamine which is an intermediate in one biosynthetic pathway to the plant hormone indole-3-acetic acid (heteroauxin).[3] Higher concentrations can be found in many Acacia species.
Tryptamine acts as a natural pesticide in plants.[4]
# Tryptamine derivatives
The most well-known tryptamines are serotonin, an important neurotransmitter, and melatonin, a hormone involved in regulating the sleep-wake cycle. Tryptamine alkaloids found in fungi, plants and animals are commonly used by humans for their psychotropic effects. Prominent examples include psilocybin (from "magic mushrooms") and DMT (from numerous plant sources, e.g. chacruna, often used in ayahuasca brews). Many synthetic tryptamines have also been made, including the migraine drug sumatriptan and its relatives. The tables below list some commonly encountered substituted tryptamines.
The tryptamine backbone can also be identified as part of the structure of some
more complex compounds, for example: LSD, ibogaine and yohimbine.
A thorough investigation of dozens of tryptamine compounds was published by Ann and Alexander Shulgin under the title TiHKAL.
The Abramovitch-Shapiro tryptamine synthesis is an organic reaction for the synthesis of tryptamines starting from a beta-Carboline [5] | https://www.wikidoc.org/index.php/Abramovitch-Shapiro_tryptamine_synthesis | |
644197c131eb639d2aaf9a2e6a1323401831fbef | wikidoc | Withdrawal | Withdrawal
Synonyms and keywords: Withdrawal syndrome; abstinence syndrome
# Overview
Withdrawal refers to the characteristic signs and symptoms that appear when a drug that causes physical dependence is regularly used for a long time and then suddenly discontinued or decreased in dosage. The term can also, less formally, refer to symptoms that appear after discontinuing a drug or other substance (unable to cause true physical dependence) that one has become psychologically dependent upon.
# Pathophysiology
The sustained use of many kinds of drugs causes reversible adaptations within the body that tend to lessen the drug's original effects over time, a phenomenon known as drug tolerance. To have these adaptations to a drug is to have a physical dependency on it, for when the drug is suddenly discontinued or decreased, the adaptations do not immediately disappear. Unopposed by the drug, the adaptations appear as withdrawal signs and symptoms that are generally the opposite of the drug's direct effects. Depending primarily on the drug's elimination half-life, withdrawal symptoms can appear within a few hours to several days after discontinuation.
The withdrawal symptoms associated with many recreational drugs are well-known. However, many drugs that do not generally cause euphoria, and are therefore not generally abused or thought of as addictive, also induce physical dependence with associated withdrawal. Examples include beta blockers, corticosteroids such as cortisone, many anticonvulsants and most antidepressants. Nevertheless, sudden withdrawal from these medications can be harmful or even fatal; this is why many prescription labels explicitly warn the patient not to discontinue the drug without doctor approval.
## Examples
- Delirium tremens
- Benzodiazepine withdrawal syndrome
- SSRI discontinuation syndrome
- Neonatal abstinence syndrome
# Withdrawal from Drugs of Abuse
Central to the role of nearly all drugs that are commonly abused to produce euphoria is the nucleus accumbens, the brain's "pleasure center". Neurons in the nucleus accumbens use the neurotransmitter dopamine, so while specific mechanisms vary, nearly every drug of abuse either stimulates dopamine release or enhances its activity, directly or indirectly. Sustained use of the drug results in less and less stimulation of the nucleus accumbens until eventually it produces no euphoria at all. Discontinuation of the drug then produces a withdrawal syndrome characterized by dysphoria — the opposite of euphoria — as nucleus accumbens activity declines below normal levels.
Withdrawal symptoms can vary significantly among individuals, but there are some commonalities. Subnormal activity in the nucleus accumbens is often characterized by depression, anxiety and craving, and if extreme can help drive the individual to continue the drug despite significant harm — the definition of addiction — or even to suicide.
However, addiction is to be carefully distinguished from physical dependence. Addiction is a psychological compulsion to use a drug despite harm that often persists long after all physical withdrawal symptoms have abated. On the other hand, the mere presence of even profound physical dependence does not necessarily denote addiction, e.g., in a patient using large doses of opioids to control chronic pain under medical supervision.
As the symptoms vary, some people are, for example, able to quit smoking "cold turkey" (i.e., immediately, without any tapering off) while others may never find success despite repeated efforts. However, the length and the degree of an addiction can be indicative of the severity of withdrawal.
Withdrawal is a more serious medical issue for some substances than for others. While nicotine withdrawal, for instance, is usually managed without medical intervention, attempting to give up a benzodiazepine or alcohol dependency can result in seizures and worse if not carried out properly. An instantaneous full stop to a long, constant alcohol use can lead to delirium tremens, which may be fatal.
An interesting side-note is that while physical dependence (and withdrawal on discontinuation) is virtually inevitable with the sustained use of certain classes of drugs, notably the opioids, psychological addiction is much less common. Most chronic pain patients, as mentioned earlier, are one example. There are also documented cases of soldiers who used heroin recreationally in Vietnam during the war, but who gave it up when they returned home (see Rat Park for experiments on rats showing the same results). It is thought that the severity or otherwise of withdrawal is related to the person's preconceptions about withdrawal. In other words, people can prepare to withdraw by developing a rational set of beliefs about what they are likely to experience. Self-help materials are available for this purpose.
# Withdrawal from Prescription Medicine
As mentioned earlier, many drugs should not be stopped abruptly without the advice and supervision of a physician, especially if the medication induces dependence or if the condition they are being used to treat is potentially dangerous and likely to return once medication is stopped, such as diabetes, asthma, heart conditions and many psychological or neurological conditions, like epilepsy, hypertension, schizophrenia and psychosis. To be safe, consult a doctor before discontinuing any prescription medication.
Sudden cessation of the use of an antidepressant can deepen the feel of depression significantly (see "Rebound" below), and some specific antidepressants can cause a unique set of other symptoms as well when stopped abruptly.
Discontinuation of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressants, (and the related class serotonin-norepinephrine reuptake inhibitors or SNRIs) is associated with a particular syndrome of physical and psychological symptoms known as SSRI discontinuation syndrome. Effexor (venlafaxine) and Paxil (paroxetine), both of which have relatively short half-lives in the body, are the most likely of the antidepressants to cause withdrawals. Prozac (fluoxetine), on the other hand, is the least likely of SSRI and SNRI antidepressants to cause any withdrawal symptoms, due to its exceptionally long half-life.
# Rebound
Many substances can cause rebound effects (significant return of the original symptom in absence of the original cause) when discontinued, regardless of their tendency to cause other withdrawal symptoms. Rebound depression is common among users of any antidepressant who stop the drug abruptly, whose states are sometimes worse than the original before taking medication. This is somewhat similar (though generally less intense and more drawn out) than the 'crash' that users of ecstasy, amphetamines, and other stimulants experience. Occasionally light users of opiates that would otherwise not experience much in the way of withdrawals will notice some rebound depression as well. Extended use of drugs that increase the amount of serotonin or other neurotransmitters in the brain can cause some receptors to 'turn off' temporarily or become desensitized, so, when the amount of the neurotransmitter available in the synapse returns to an otherwise normal state, there are fewer receptors to attach to, causing feelings of depression until the brain re-adjusts.
Other drugs that commonly cause rebound are:
- Nasal decongestants, such as Afrin (oxymetazoline) and Otrivin (xylometazoline), which can cause rebound congestion if used for more than a few days
- Many analgesics including Advil, Motrin (ibuprofen), Aspirin (acetylsalicylic acid), Tylenol (acetaminophen or paracetamol), and some prescription but non-narcotic painkillers, which can cause rebound headaches when taken for extended periods of time.
- Sedatives and benzodiazepines, which can cause rebound insomnia when used regularly as sleep aids.
With these drugs, the only way to relieve the rebound symptoms is to stop the medication causing them and weather the symptoms for a few days; if the original cause for the symptoms is no longer present, the rebound effects will go away on their own.
# Neonatal Abstinence Syndrome
Neonatal abstinence syndrome (NAS) is a withdrawal syndrome of infants, caused by administration of drugs. There are two types of NAS, prenatal and postnatal. Prenatal NAS is caused by substance abuse by the mother, while postnatal NAS is caused by discontinuation of drugs directly to the infant.
The drugs involved are e.g. opioids, selective serotonin reuptake inhibitors (SSRIs) and alcoholic beverages.
# Pseudoabstinence
Pseudoabstinence is used by some authors to describe signs of withdrawal although the dose remains constant. Such signs may arise in use of benzodiazepines and amphetamine.
# Related Chapters
- Chemical dependency
- Drug tolerance | Withdrawal
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Withdrawal syndrome; abstinence syndrome
# Overview
Withdrawal refers to the characteristic signs and symptoms that appear when a drug that causes physical dependence is regularly used for a long time and then suddenly discontinued or decreased in dosage. The term can also, less formally, refer to symptoms that appear after discontinuing a drug or other substance (unable to cause true physical dependence) that one has become psychologically dependent upon.
# Pathophysiology
The sustained use of many kinds of drugs causes reversible adaptations within the body that tend to lessen the drug's original effects over time, a phenomenon known as drug tolerance. To have these adaptations to a drug is to have a physical dependency on it, for when the drug is suddenly discontinued or decreased, the adaptations do not immediately disappear. Unopposed by the drug, the adaptations appear as withdrawal signs and symptoms that are generally the opposite of the drug's direct effects. Depending primarily on the drug's elimination half-life, withdrawal symptoms can appear within a few hours to several days after discontinuation.
The withdrawal symptoms associated with many recreational drugs are well-known. However, many drugs that do not generally cause euphoria, and are therefore not generally abused or thought of as addictive, also induce physical dependence with associated withdrawal. Examples include beta blockers, corticosteroids such as cortisone, many anticonvulsants and most antidepressants. Nevertheless, sudden withdrawal from these medications can be harmful or even fatal; this is why many prescription labels explicitly warn the patient not to discontinue the drug without doctor approval.
## Examples
- Delirium tremens
- Benzodiazepine withdrawal syndrome
- SSRI discontinuation syndrome
- Neonatal abstinence syndrome
# Withdrawal from Drugs of Abuse
Central to the role of nearly all drugs that are commonly abused to produce euphoria is the nucleus accumbens, the brain's "pleasure center". Neurons in the nucleus accumbens use the neurotransmitter dopamine, so while specific mechanisms vary, nearly every drug of abuse either stimulates dopamine release or enhances its activity, directly or indirectly. Sustained use of the drug results in less and less stimulation of the nucleus accumbens until eventually it produces no euphoria at all. Discontinuation of the drug then produces a withdrawal syndrome characterized by dysphoria — the opposite of euphoria — as nucleus accumbens activity declines below normal levels.
Withdrawal symptoms can vary significantly among individuals, but there are some commonalities. Subnormal activity in the nucleus accumbens is often characterized by depression, anxiety and craving, and if extreme can help drive the individual to continue the drug despite significant harm — the definition of addiction — or even to suicide.
However, addiction is to be carefully distinguished from physical dependence. Addiction is a psychological compulsion to use a drug despite harm that often persists long after all physical withdrawal symptoms have abated. On the other hand, the mere presence of even profound physical dependence does not necessarily denote addiction, e.g., in a patient using large doses of opioids to control chronic pain under medical supervision.
As the symptoms vary, some people are, for example, able to quit smoking "cold turkey" (i.e., immediately, without any tapering off) while others may never find success despite repeated efforts. However, the length and the degree of an addiction can be indicative of the severity of withdrawal.
Withdrawal is a more serious medical issue for some substances than for others. While nicotine withdrawal, for instance, is usually managed without medical intervention, attempting to give up a benzodiazepine or alcohol dependency can result in seizures and worse if not carried out properly. An instantaneous full stop to a long, constant alcohol use can lead to delirium tremens, which may be fatal.
An interesting side-note is that while physical dependence (and withdrawal on discontinuation) is virtually inevitable with the sustained use of certain classes of drugs, notably the opioids, psychological addiction is much less common. Most chronic pain patients, as mentioned earlier, are one example. There are also documented cases of soldiers who used heroin recreationally in Vietnam during the war, but who gave it up when they returned home (see Rat Park for experiments on rats showing the same results). It is thought that the severity or otherwise of withdrawal is related to the person's preconceptions about withdrawal. In other words, people can prepare to withdraw by developing a rational set of beliefs about what they are likely to experience. Self-help materials are available for this purpose.
# Withdrawal from Prescription Medicine
As mentioned earlier, many drugs should not be stopped abruptly[1] without the advice and supervision of a physician, especially if the medication induces dependence or if the condition they are being used to treat is potentially dangerous and likely to return once medication is stopped, such as diabetes, asthma, heart conditions and many psychological or neurological conditions, like epilepsy, hypertension, schizophrenia and psychosis. To be safe, consult a doctor before discontinuing any prescription medication.
Sudden cessation of the use of an antidepressant can deepen the feel of depression significantly (see "Rebound" below), and some specific antidepressants can cause a unique set of other symptoms as well when stopped abruptly.
Discontinuation of selective serotonin reuptake inhibitors (SSRIs), the most commonly prescribed class of antidepressants, (and the related class serotonin-norepinephrine reuptake inhibitors or SNRIs) is associated with a particular syndrome of physical and psychological symptoms known as SSRI discontinuation syndrome. Effexor (venlafaxine) and Paxil (paroxetine), both of which have relatively short half-lives in the body, are the most likely of the antidepressants to cause withdrawals. Prozac (fluoxetine), on the other hand, is the least likely of SSRI and SNRI antidepressants to cause any withdrawal symptoms, due to its exceptionally long half-life.
# Rebound
Many substances can cause rebound effects (significant return of the original symptom in absence of the original cause) when discontinued, regardless of their tendency to cause other withdrawal symptoms. Rebound depression is common among users of any antidepressant who stop the drug abruptly, whose states are sometimes worse than the original before taking medication. This is somewhat similar (though generally less intense and more drawn out) than the 'crash' that users of ecstasy, amphetamines, and other stimulants experience. Occasionally light users of opiates that would otherwise not experience much in the way of withdrawals will notice some rebound depression as well. Extended use of drugs that increase the amount of serotonin or other neurotransmitters in the brain can cause some receptors to 'turn off' temporarily or become desensitized, so, when the amount of the neurotransmitter available in the synapse returns to an otherwise normal state, there are fewer receptors to attach to, causing feelings of depression until the brain re-adjusts.
Other drugs that commonly cause rebound are:
- Nasal decongestants, such as Afrin (oxymetazoline) and Otrivin (xylometazoline), which can cause rebound congestion if used for more than a few days
- Many analgesics including Advil, Motrin (ibuprofen), Aspirin (acetylsalicylic acid), Tylenol (acetaminophen or paracetamol), and some prescription but non-narcotic painkillers, which can cause rebound headaches when taken for extended periods of time.
- Sedatives and benzodiazepines, which can cause rebound insomnia when used regularly as sleep aids.
With these drugs, the only way to relieve the rebound symptoms is to stop the medication causing them and weather the symptoms for a few days; if the original cause for the symptoms is no longer present, the rebound effects will go away on their own.
# Neonatal Abstinence Syndrome
Neonatal abstinence syndrome (NAS) is a withdrawal syndrome of infants, caused by administration of drugs. There are two types of NAS, prenatal and postnatal. Prenatal NAS is caused by substance abuse by the mother, while postnatal NAS is caused by discontinuation of drugs directly to the infant.
The drugs involved are e.g. opioids, selective serotonin reuptake inhibitors (SSRIs) and alcoholic beverages.
# Pseudoabstinence
Pseudoabstinence is used by some authors to describe signs of withdrawal although the dose remains constant. Such signs may arise in use of benzodiazepines and amphetamine.
# Related Chapters
- Chemical dependency
- Drug tolerance | https://www.wikidoc.org/index.php/Abstinence_syndrome | |
da5d6de8a4145016412b513f5df9c92b50a2c1d8 | wikidoc | Acebutolol | Acebutolol
- Dosing Information
- The initial dosage of acebutolol hydrochloride capsules in uncomplicated mild-to-moderate hypertension is 400 mg. This can be given as a single daily dose, but in occasional patients twice daily dosing may be required for adequate 24-hour blood-pressure control. An optimal response is usually achieved with dosages of 400 to 800 mg/day, although some patients have been maintained on as little as 200 mg/day. Patients with more severe hypertension or who have demonstrated inadequate control may respond to a total of 1200 mg daily (administered b.i.d.), or to the addition of a second antihypertensive agent. Beta-1 selectivity diminishes as dosage is increased.
- Dosing Information
- The usual initial dosage of acebutolol hydrochloride capsules is 400 mg daily given as 200 mg b.i.d. Dosage should be increased gradually until an optimal clinical response is obtained, generally at 600 to 1200 mg/day. If treatment is to be discontinued, the dosage should be reduced gradually over a period of about 2 weeks.
- Dosing information
- Older patients have an approximately 2-fold increase in bioavailability and may require lower maintenance doses. Doses above 800 mg/day should be avoided in the elderly.
- Dosing Information
- Monotherapy: 600 to 1600 mg/day.
- Acebutolol 100 mg + oral nifedipine 10 mg.
- Dosing Information
- Acebutolol 200 mg PO q12h + digoxin initial dose of 1 mg PO/IV followed by 0.25 mg/day (maintenance).
- Dosing information
- 200 milligrams mg/day.
- Second-degree AV heart block
- Third-degree AV heart block
- Overt cardiac failure
- Cardiogenic shock
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt cardiac failure, acebutolol can be used with caution in patients with a history of heart failure who are controlled with digitalis and/or diuretics. Both digitalis and acebutolol impair AV conduction. If cardiac failure persists, therapy with acebutolol should be withdrawn.
In patients with aortic valve disease or mitral valve disease or compromised left ventricular function, continued depression of the myocardium with beta-blocking agents over a period of time may lead to cardiac failure. At the first signs of failure, patients should be digitalized and/or be given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalization and/or diuretic, acebutolol therapy should be withdrawn.
Following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbation of angina pectoris and, in some cases, myocardial infarction and death have been reported. Therefore, such patients should be cautioned against interruption of therapy without a physician's advice. Even in the absence of overt ischemic heart disease, when discontinuation of acebutolol is planned, the patient should be carefully observed, and should be advised to limit physical activity to a minimum while acebutolol is gradually withdrawn over a period of about 2 weeks. (If therapy with an alternative beta-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of beta-blocking therapy.) If an exacerbation of angina pectoris occurs, antianginal therapy should be restarted immediately in full doses and the patient hospitalized until his condition stabilizes.
Treatment with beta-antagonists reduces cardiac output and can precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease. Caution should be exercised with such patients, and they should be observed closely for evidence of progression of arterial obstruction.
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE A BETA-BLOCKER. Because of its relative β1-selectivity, however, low doses of acebutolol may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. Since β1-selectivity is not absolute and is dose dependent, the lowest possible dose of acebutolol should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose-interval. A bronchodilator, such as a theophylline or a β2-stimulant, should be made available in advance with instructions concerning its use.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Beta-blockers may potentiate insulin-induced hypoglycemia and mask some of its manifestations such as tachycardia; however, dizziness and sweating are usually not significantly affected. Diabetic patients should be warned of the possibility of masked hypoglycemia.
Beta-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom acebutolol therapy is to be withdrawn should be monitored closely.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
The following table shows the frequency of treatment-related side effects derived from controlled clinical trials in patients with hypertension, angina pectoris, and arrhythmia. These patients received acebutolol, propranolol, or hydrochlorothiazide as monotherapy, or placebo.
The following selected (potentially important) side effects were seen in up to 2% of acebutolol patients:
- Cardiovascular: Hypotension, bradycardia, heart failure.
- Central Nervous System: Anxiety, hyperesthesia, hypoesthesia, impotence.
- Dermatological: Pruritus.
- Gastrointestinal: Vomiting, abdominal pain.
- Genitourinary: Dysuria, nocturia.
- Liver and Biliary System: A small number of cases of liver abnormalities (increased SGOT, SGPT, LDH) have been reported in association with acebutolol therapy. In some cases increased bilirubin or alkaline phosphatase, fever, malaise, dark urine, anorexia, nausea, headache, and/or other symptoms have been reported. In some of the reported cases, the symptoms and signs were confirmed by rechallenge with acebutolol. The abnormalities were reversible upon cessation of acebutolol therapy.
- Musculoskeletal: Back pain, joint pain.
- Respiratory: Pharyngitis, wheezing.
- Special Senses: Conjunctivitis, dry eye, eye pain.
- Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.
The incidence of drug-related adverse effects (volunteered and solicited) according to acebutolol dose is shown below. (Data from 266 hypertensive patients treated for 3 months on a constant dose.)
In addition, certain adverse effects not listed above have been reported with other beta-blocking agents and should also be considered as potential adverse effects of acebutolol.
- Central Nervous System: Reversible mental depression progressing to catatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics).
- Cardiovascular: Intensification of AV block.
- Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.
- Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis.
- Miscellaneous: Reversible alopecia and Peyronie's disease.
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with acebutolol during investigational use and extensive foreign clinical experience.
Acebutolol, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA). In prospective clinical trials, patients receiving acebutolol had a dose-dependent increase in the development of positive ANA titers and the overall incidence was higher than that observed with propranolol. Symptoms (generally persistent arthralgias and myalgias) related to this laboratory abnormality were infrequent (less than 1% with both drugs). Symptoms and ANA titers were reversible upon discontinuation of treatment.
- Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.
- No significant interactions with:
- Digoxin
- Hydrochlorothiazide
- Hydralazine
- Sulfinpyrazone
- Oral contraceptives
- Tolbutamide
- Warfarin
- Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Studies in humans have shown that both acebutolol and diacetolol cross the placenta. Neonates of mothers who have received acebutolol during pregnancy have reduced birth weight, decreased blood pressure, and decreased heart rate. In the newborn the elimination half-life of acebutolol was 6 to 14 hours, while the half-life of diacetolol was 24 to 30 hours for the first 24 hours after birth, followed by a half-life of 12 to 16 hours. Adequate facilities for monitoring these infants at birth should be available.
- Empty stomach by emesis or lavage.
- Bradycardia: IV atropine (1 mg to 3 mg in divided doses). If antivagal response is inadequate, administer isoproterenol cautiously since larger than usual doses of isoproterenol may be required.
- Persistent hypotension in spite of correction of bradycardia: Administer vasopressor (e.g., epinephrine, norepinephrine, dopamine, or dobutamine) with frequent monitoring of blood pressure and heart rate.
- Bronchospasm: A theophylline derivative, such as aminophylline and/or parenteral β2-stimulant, such as terbutaline.
- Cardiac failure: Digitalize the patient and/or administer a diuretic. It has been reported that glucagon is useful in this situation.
Acebutolol is dialyzable.
Acebutolol hydrochloride, USP is a white or slightly off-white powder freely soluble in water, and less soluble in alcohol. Chemically it is defined as the hydrochloride salt of (±) N-propoxy]phenyl] butanamide.
The β1-selectivity of acebutolol has also been demonstrated on the basis of the following vascular and bronchial effects:
Acebutolol has less antagonistic effects on peripheral vascular β2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists.
In single-dose studies in asthmatics examining effects of various beta-blockers on pulmonary function, low doses of acebutolol produce less evidence of bronchoconstriction and less reduction of β2 agonist, bronchodilating effects, than nonselective agents like propranolol but more than atenolol.
ISA has been observed with acebutolol in man, as shown by a slightly smaller (about three beats per minute) decrease in resting heart rate when compared to equivalent beta-blocking doses of propranolol, metoprolol or atenolol. Chronic therapy with acebutolol induced no significant alteration in the blood lipid profile.
Acebutolol has been shown to delay AV conduction time and to increase the refractoriness of the AV node without significantly affecting sinus node recovery time, atrial refractory period, or the HV conduction time. The membrane-stabilizing effect of acebutolol is not manifest at the doses used clinically.
Significant reductions in resting and exercise heart rates and systolic blood pressures have been observed 1.5 hours after acebutolol administration with maximal effects occurring between 3 and 8 hours postdosing in normal volunteers. Acebutolol has demonstrated a significant effect on exercise-induced tachycardia 24 to 30 hours after drug administration.
There are significant correlations between plasma levels of acebutolol and both the reduction in resting heart rate and the percent of beta-blockade of exercise-induced tachycardia. The antihypertensive effect of acebutolol has been shown in double-blind controlled studies to be superior to placebo and similar to propranolol and hydrochlorothiazide. In addition, patients responding to acebutolol administered twice daily had a similar response whether the dosage regimen was changed to once daily administration or continued on a b.i.d. regimen. Most patients responded to 400 to 800 mg/day in divided doses.
The antiarrhythmic effect of acebutolol was compared with placebo, propranolol, and quinidine. Compared with placebo, acebutolol significantly reduced mean total ventricular ectopic beats (VEB), paired VEB, multiform VEB, R-on-T beats, and ventricular tachycardia (VT). Both acebutolol and propranolol significantly reduced mean total and paired VEB and VT. Acebutolol and quinidine significantly reduced resting total and complex VEB; the antiarrhythmic efficacy of acebutolol was also observed during exercise.
The plasma elimination half-life of acebutolol is approximately 3 to 4 hours, while that of its metabolite, diacetolol, is 8 to 13 hours. The time to reach peak concentration for acebutolol is 2.5 hours and for diacetolol, after oral administration of acebutolol hydrochloride, 3.5 hours.
Within the single oral dose range of 200 mg to 400 mg, the kinetics are dose proportional. However, this linearity is not seen at higher doses, probably due to saturation of hepatic biotransformation sites. In addition, after multiple dosing the lack of linearity is also seen by AUC increases of approximately 100% as compared to single oral dosing. Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall.
Acebutolol hydrochloride has a low binding affinity for plasma proteins (about 26%). Acebutolol and its metabolite, diacetolol, are relatively hydrophilic and, therefore, only minimal quantities have been detected in the cerebrospinal fluid (CSF).
Drug interaction studies with tolbutamide and warfarin indicated no influence on the therapeutic effects of these compounds. Digoxin and hydrochlorothiazide plasma levels were not affected by concomitant acebutolol administration. The kinetics of acebutolol were not significantly altered by concomitant administration of hydrochlorothiazide, hydralazine, sulfinpyrazone, or oral contraceptives.
In patients with renal impairment, there is no effect on the elimination half-life of acebutolol, but there is decreased elimination of the metabolite, diacetolol, resulting in a 2- to 3-fold increase in its half-life. For this reason, the drug should be administered with caution in patients with renal insufficiency. Acebutolol and its major metabolite are dialyzable.
Acebutolol crosses the placental barrier, and is secreted in breast milk.
In geriatric patients, the bioavailability of acebutolol and its metabolite is increased, approximately 2-fold, probably due to decreases in the first-pass metabolism and renal function in the elderly.
- Reduction in the resting heart rate and decrease in exercise-induced tachycardia
- Reduction in cardiac output at rest and after exercise
- Reduction of systolic blood pressure and diastolic blood pressure at rest and postexercise
- Inhibition of isoproterenol-induced tachycardia.
- 200 mg, opaque purple and orange capsule marked "RP 700" and "Sectral® 200" NDC 67857-700-01, in bottles of 100 capsules.
- 400 mg, opaque brown and orange capsule marked "RP 701" and "Sectral® 400"
NDC 67857-701-01, in bottles of 100 capsules.
- Protect from light
- Dispense in a light-resistant, tight container
- Use carton to protect contents from light
Patients should also be warned of possible severe hypertensive reactions from concomitant use of alpha-adrenergic stimulants, such as the nasal decongestants commonly used in OTC cold preparations and nasal drops.
- ↑ Singh BN, Thoden WR, Ward A (1985). "Acebutolol. A review of its pharmacological properties and therapeutic efficacy in hypertension, angina pectoris and arrhythmia". Drugs. 29 (6): 531–69. PMID 3891306.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Kaul S, Hecht HS, Seidman R, Hopkins J, Singh BN (1984). "Comparative effects of oral acebutolol and propranolol at rest and during exercise in ischemic heart disease: double-blind placebo crossover study utilizing radionuclide ventriculography". Am Heart J. 108 (3 Pt 1): 469–74. PMID 6382987.CS1 maint: Multiple names: authors list (link)
- ↑ Pfisterer M, Müller-Brand J, Burkart F (1982). "Combined acebutolol/nifedipine therapy in patients with chronic coronary artery disease: additional improvement of ischemia-induced left ventricular dysfunction". Am J Cardiol. 49 (5): 1259–66. PMID 7064850.CS1 maint: Multiple names: authors list (link)
- ↑ Kowey PR, Dalessandro DA, Herbertson R, Briggs B, Wertan MA, Rials SJ; et al. (1997). "Effectiveness of digitalis with or without acebutolol in preventing atrial arrhythmias after coronary artery surgery". Am J Cardiol. 79 (8): 1114–7. PMID 9114777.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Cohen TJ, Cayenne S, Black M, Doolittle S, Ibrahim B, Quan W (1999). "The effects of intrinsic sympathomimetic activity on beta-blocker efficacy for treatment of neurocardiogenic syncope". J Invasive Cardiol. 11 (7): 457–60. PMID 10745573.CS1 maint: Multiple names: authors list (link) | Acebutolol
- Dosing Information
- The initial dosage of acebutolol hydrochloride capsules in uncomplicated mild-to-moderate hypertension is 400 mg. This can be given as a single daily dose, but in occasional patients twice daily dosing may be required for adequate 24-hour blood-pressure control. An optimal response is usually achieved with dosages of 400 to 800 mg/day, although some patients have been maintained on as little as 200 mg/day. Patients with more severe hypertension or who have demonstrated inadequate control may respond to a total of 1200 mg daily (administered b.i.d.), or to the addition of a second antihypertensive agent. Beta-1 selectivity diminishes as dosage is increased.
- Dosing Information
- The usual initial dosage of acebutolol hydrochloride capsules is 400 mg daily given as 200 mg b.i.d. Dosage should be increased gradually until an optimal clinical response is obtained, generally at 600 to 1200 mg/day. If treatment is to be discontinued, the dosage should be reduced gradually over a period of about 2 weeks.
- Dosing information
- Older patients have an approximately 2-fold increase in bioavailability and may require lower maintenance doses. Doses above 800 mg/day should be avoided in the elderly.
- Dosing Information
- Monotherapy: 600 to 1600 mg/day.[1][2]
- Acebutolol 100 mg + oral nifedipine 10 mg.[3]
- Dosing Information
- Acebutolol 200 mg PO q12h + digoxin initial dose of 1 mg PO/IV followed by 0.25 mg/day (maintenance).[4]
- Dosing information
- 200 milligrams mg/day.[5]
- Second-degree AV heart block
- Third-degree AV heart block
- Overt cardiac failure
- Cardiogenic shock
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by beta-adrenergic receptor blockade may precipitate more severe failure. Although beta-blockers should be avoided in overt cardiac failure, acebutolol can be used with caution in patients with a history of heart failure who are controlled with digitalis and/or diuretics. Both digitalis and acebutolol impair AV conduction. If cardiac failure persists, therapy with acebutolol should be withdrawn.
In patients with aortic valve disease or mitral valve disease or compromised left ventricular function, continued depression of the myocardium with beta-blocking agents over a period of time may lead to cardiac failure. At the first signs of failure, patients should be digitalized and/or be given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalization and/or diuretic, acebutolol therapy should be withdrawn.
Following abrupt cessation of therapy with certain beta-blocking agents in patients with coronary artery disease, exacerbation of angina pectoris and, in some cases, myocardial infarction and death have been reported. Therefore, such patients should be cautioned against interruption of therapy without a physician's advice. Even in the absence of overt ischemic heart disease, when discontinuation of acebutolol is planned, the patient should be carefully observed, and should be advised to limit physical activity to a minimum while acebutolol is gradually withdrawn over a period of about 2 weeks. (If therapy with an alternative beta-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of beta-blocking therapy.) If an exacerbation of angina pectoris occurs, antianginal therapy should be restarted immediately in full doses and the patient hospitalized until his condition stabilizes.
Treatment with beta-antagonists reduces cardiac output and can precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease. Caution should be exercised with such patients, and they should be observed closely for evidence of progression of arterial obstruction.
PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE A BETA-BLOCKER. Because of its relative β1-selectivity, however, low doses of acebutolol may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate, alternative treatment. Since β1-selectivity is not absolute and is dose dependent, the lowest possible dose of acebutolol should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose-interval. A bronchodilator, such as a theophylline or a β2-stimulant, should be made available in advance with instructions concerning its use.
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.
Beta-blockers may potentiate insulin-induced hypoglycemia and mask some of its manifestations such as tachycardia; however, dizziness and sweating are usually not significantly affected. Diabetic patients should be warned of the possibility of masked hypoglycemia.
Beta-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. Abrupt withdrawal of beta-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom acebutolol therapy is to be withdrawn should be monitored closely.
While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.
The following table shows the frequency of treatment-related side effects derived from controlled clinical trials in patients with hypertension, angina pectoris, and arrhythmia. These patients received acebutolol, propranolol, or hydrochlorothiazide as monotherapy, or placebo.
The following selected (potentially important) side effects were seen in up to 2% of acebutolol patients:
- Cardiovascular: Hypotension, bradycardia, heart failure.
- Central Nervous System: Anxiety, hyperesthesia, hypoesthesia, impotence.
- Dermatological: Pruritus.
- Gastrointestinal: Vomiting, abdominal pain.
- Genitourinary: Dysuria, nocturia.
- Liver and Biliary System: A small number of cases of liver abnormalities (increased SGOT, SGPT, LDH) have been reported in association with acebutolol therapy. In some cases increased bilirubin or alkaline phosphatase, fever, malaise, dark urine, anorexia, nausea, headache, and/or other symptoms have been reported. In some of the reported cases, the symptoms and signs were confirmed by rechallenge with acebutolol. The abnormalities were reversible upon cessation of acebutolol therapy.
- Musculoskeletal: Back pain, joint pain.
- Respiratory: Pharyngitis, wheezing.
- Special Senses: Conjunctivitis, dry eye, eye pain.
- Autoimmune: In extremely rare instances, systemic lupus erythematosus has been reported.
The incidence of drug-related adverse effects (volunteered and solicited) according to acebutolol dose is shown below. (Data from 266 hypertensive patients treated for 3 months on a constant dose.)
In addition, certain adverse effects not listed above have been reported with other beta-blocking agents and should also be considered as potential adverse effects of acebutolol.
- Central Nervous System: Reversible mental depression progressing to catatonia (an acute syndrome characterized by disorientation for time and place), short-term memory loss, emotional lability, slightly clouded sensorium, and decreased performance (neuropsychometrics).
- Cardiovascular: Intensification of AV block.
- Allergic: Erythematous rash, fever combined with aching and sore throat, laryngospasm, and respiratory distress.
- Hematologic: Agranulocytosis, nonthrombocytopenic purpura and thrombocytopenic purpura.
- Gastrointestinal: Mesenteric arterial thrombosis and ischemic colitis.
- Miscellaneous: Reversible alopecia and Peyronie's disease.
The oculomucocutaneous syndrome associated with the beta blocker practolol has not been reported with acebutolol during investigational use and extensive foreign clinical experience.
Acebutolol, like other beta-blockers, has been associated with the development of antinuclear antibodies (ANA). In prospective clinical trials, patients receiving acebutolol had a dose-dependent increase in the development of positive ANA titers and the overall incidence was higher than that observed with propranolol. Symptoms (generally persistent arthralgias and myalgias) related to this laboratory abnormality were infrequent (less than 1% with both drugs). Symptoms and ANA titers were reversible upon discontinuation of treatment.
- Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.
- No significant interactions with:
- Digoxin
- Hydrochlorothiazide
- Hydralazine
- Sulfinpyrazone
- Oral contraceptives
- Tolbutamide
- Warfarin
- Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
Studies in humans have shown that both acebutolol and diacetolol cross the placenta. Neonates of mothers who have received acebutolol during pregnancy have reduced birth weight, decreased blood pressure, and decreased heart rate. In the newborn the elimination half-life of acebutolol was 6 to 14 hours, while the half-life of diacetolol was 24 to 30 hours for the first 24 hours after birth, followed by a half-life of 12 to 16 hours. Adequate facilities for monitoring these infants at birth should be available.
- Empty stomach by emesis or lavage.
- Bradycardia: IV atropine (1 mg to 3 mg in divided doses). If antivagal response is inadequate, administer isoproterenol cautiously since larger than usual doses of isoproterenol may be required.
- Persistent hypotension in spite of correction of bradycardia: Administer vasopressor (e.g., epinephrine, norepinephrine, dopamine, or dobutamine) with frequent monitoring of blood pressure and heart rate.
- Bronchospasm: A theophylline derivative, such as aminophylline and/or parenteral β2-stimulant, such as terbutaline.
- Cardiac failure: Digitalize the patient and/or administer a diuretic. It has been reported that glucagon is useful in this situation.
Acebutolol is dialyzable.
Acebutolol hydrochloride, USP is a white or slightly off-white powder freely soluble in water, and less soluble in alcohol. Chemically it is defined as the hydrochloride salt of (±) N-[3-Acetyl-4-[2-hydroxy-3-[(1-methylethyl)amino]propoxy]phenyl] butanamide.
The β1-selectivity of acebutolol has also been demonstrated on the basis of the following vascular and bronchial effects:
Acebutolol has less antagonistic effects on peripheral vascular β2-receptors at rest and after epinephrine stimulation than nonselective beta-antagonists.
In single-dose studies in asthmatics examining effects of various beta-blockers on pulmonary function, low doses of acebutolol produce less evidence of bronchoconstriction and less reduction of β2 agonist, bronchodilating effects, than nonselective agents like propranolol but more than atenolol.
ISA has been observed with acebutolol in man, as shown by a slightly smaller (about three beats per minute) decrease in resting heart rate when compared to equivalent beta-blocking doses of propranolol, metoprolol or atenolol. Chronic therapy with acebutolol induced no significant alteration in the blood lipid profile.
Acebutolol has been shown to delay AV conduction time and to increase the refractoriness of the AV node without significantly affecting sinus node recovery time, atrial refractory period, or the HV conduction time. The membrane-stabilizing effect of acebutolol is not manifest at the doses used clinically.
Significant reductions in resting and exercise heart rates and systolic blood pressures have been observed 1.5 hours after acebutolol administration with maximal effects occurring between 3 and 8 hours postdosing in normal volunteers. Acebutolol has demonstrated a significant effect on exercise-induced tachycardia 24 to 30 hours after drug administration.
There are significant correlations between plasma levels of acebutolol and both the reduction in resting heart rate and the percent of beta-blockade of exercise-induced tachycardia. The antihypertensive effect of acebutolol has been shown in double-blind controlled studies to be superior to placebo and similar to propranolol and hydrochlorothiazide. In addition, patients responding to acebutolol administered twice daily had a similar response whether the dosage regimen was changed to once daily administration or continued on a b.i.d. regimen. Most patients responded to 400 to 800 mg/day in divided doses.
The antiarrhythmic effect of acebutolol was compared with placebo, propranolol, and quinidine. Compared with placebo, acebutolol significantly reduced mean total ventricular ectopic beats (VEB), paired VEB, multiform VEB, R-on-T beats, and ventricular tachycardia (VT). Both acebutolol and propranolol significantly reduced mean total and paired VEB and VT. Acebutolol and quinidine significantly reduced resting total and complex VEB; the antiarrhythmic efficacy of acebutolol was also observed during exercise.
The plasma elimination half-life of acebutolol is approximately 3 to 4 hours, while that of its metabolite, diacetolol, is 8 to 13 hours. The time to reach peak concentration for acebutolol is 2.5 hours and for diacetolol, after oral administration of acebutolol hydrochloride, 3.5 hours.
Within the single oral dose range of 200 mg to 400 mg, the kinetics are dose proportional. However, this linearity is not seen at higher doses, probably due to saturation of hepatic biotransformation sites. In addition, after multiple dosing the lack of linearity is also seen by AUC increases of approximately 100% as compared to single oral dosing. Elimination via renal excretion is approximately 30% to 40% and by non-renal mechanisms 50% to 60%, which includes excretion into the bile and direct passage through the intestinal wall.
Acebutolol hydrochloride has a low binding affinity for plasma proteins (about 26%). Acebutolol and its metabolite, diacetolol, are relatively hydrophilic and, therefore, only minimal quantities have been detected in the cerebrospinal fluid (CSF).
Drug interaction studies with tolbutamide and warfarin indicated no influence on the therapeutic effects of these compounds. Digoxin and hydrochlorothiazide plasma levels were not affected by concomitant acebutolol administration. The kinetics of acebutolol were not significantly altered by concomitant administration of hydrochlorothiazide, hydralazine, sulfinpyrazone, or oral contraceptives.
In patients with renal impairment, there is no effect on the elimination half-life of acebutolol, but there is decreased elimination of the metabolite, diacetolol, resulting in a 2- to 3-fold increase in its half-life. For this reason, the drug should be administered with caution in patients with renal insufficiency. Acebutolol and its major metabolite are dialyzable.
Acebutolol crosses the placental barrier, and is secreted in breast milk.
In geriatric patients, the bioavailability of acebutolol and its metabolite is increased, approximately 2-fold, probably due to decreases in the first-pass metabolism and renal function in the elderly.
- Reduction in the resting heart rate and decrease in exercise-induced tachycardia
- Reduction in cardiac output at rest and after exercise
- Reduction of systolic blood pressure and diastolic blood pressure at rest and postexercise
- Inhibition of isoproterenol-induced tachycardia.
- 200 mg, opaque purple and orange capsule marked "RP 700" and "Sectral® 200" NDC 67857-700-01, in bottles of 100 capsules.
- 400 mg, opaque brown and orange capsule marked "RP 701" and "Sectral® 400"
NDC 67857-701-01, in bottles of 100 capsules.
- Protect from light
- Dispense in a light-resistant, tight container
- Use carton to protect contents from light
Patients should also be warned of possible severe hypertensive reactions from concomitant use of alpha-adrenergic stimulants, such as the nasal decongestants commonly used in OTC cold preparations and nasal drops.
- ↑ Singh BN, Thoden WR, Ward A (1985). "Acebutolol. A review of its pharmacological properties and therapeutic efficacy in hypertension, angina pectoris and arrhythmia". Drugs. 29 (6): 531–69. PMID 3891306.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Kaul S, Hecht HS, Seidman R, Hopkins J, Singh BN (1984). "Comparative effects of oral acebutolol and propranolol at rest and during exercise in ischemic heart disease: double-blind placebo crossover study utilizing radionuclide ventriculography". Am Heart J. 108 (3 Pt 1): 469–74. PMID 6382987.CS1 maint: Multiple names: authors list (link)
- ↑ Pfisterer M, Müller-Brand J, Burkart F (1982). "Combined acebutolol/nifedipine therapy in patients with chronic coronary artery disease: additional improvement of ischemia-induced left ventricular dysfunction". Am J Cardiol. 49 (5): 1259–66. PMID 7064850.CS1 maint: Multiple names: authors list (link)
- ↑ Kowey PR, Dalessandro DA, Herbertson R, Briggs B, Wertan MA, Rials SJ; et al. (1997). "Effectiveness of digitalis with or without acebutolol in preventing atrial arrhythmias after coronary artery surgery". Am J Cardiol. 79 (8): 1114–7. PMID 9114777.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Cohen TJ, Cayenne S, Black M, Doolittle S, Ibrahim B, Quan W (1999). "The effects of intrinsic sympathomimetic activity on beta-blocker efficacy for treatment of neurocardiogenic syncope". J Invasive Cardiol. 11 (7): 457–60. PMID 10745573.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Acebutolol | |
2a009a97ffee63971031dc788a1b31bb15609ee3 | wikidoc | Acetabulum | Acetabulum
The acetabulum is a concave surface of the pelvis. The head of the femur meets with the pelvis at the acetabulum, forming the hip joint.
# Structure
There are three bones of the os coxae (hip bone) that come together to form the acetabulum. Contributing a little more than two-fifths of the structure is the ischium, which provides lower and side boundaries to the acetabulum. The ilium forms the upper boundary, providing a little less than two-fifths of the structure of the acetabulum. The rest is formed by the pubis, near the midline.
It is bounded by a prominent uneven rim, which is thick and strong above, and serves for the attachment of the glenoidal labrum (cotyloid ligament), which contracts its opening, and deepens the surface for formation of the hip joint. At the lower part of the acetabulum is the acetabular notch, which is continuous with a circular depression, the acetabular fossa, at the bottom of the cavity of the acetabulum. The rest of the acetabulum is formed by a curved, crescent-moon shaped surface, the lunate surface, where the joint is made with the head of the femur. Its counterpart in the pectoral girdle is the glenoid fossa.
In reptiles and in birds, the acetabula are deep sockets.
# Etymology
The word acetabulum means "little vinegar cup", and was the Latin word for a small vessel for storing vinegar (see acetabulum). The word was later also used as a unit of volume, equal to roughly 270 ml.
# Additional images
- Right hip bone. External surface.
- Plan of ossification of the hip bone.
- Symphysis pubis exposed by a coronal section.
- Left hip-joint, opened by removing the floor of the acetabulum from within the pelvis.
- Hip-joint, front view.
- Capsule of hip-joint (distended). Posterior aspect.
- Structures surrounding right hip-joint. | Acetabulum
Template:Infobox Bone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The acetabulum is a concave surface of the pelvis. The head of the femur meets with the pelvis at the acetabulum, forming the hip joint.
# Structure
There are three bones of the os coxae (hip bone) that come together to form the acetabulum. Contributing a little more than two-fifths of the structure is the ischium, which provides lower and side boundaries to the acetabulum. The ilium forms the upper boundary, providing a little less than two-fifths of the structure of the acetabulum. The rest is formed by the pubis, near the midline.
It is bounded by a prominent uneven rim, which is thick and strong above, and serves for the attachment of the glenoidal labrum (cotyloid ligament), which contracts its opening, and deepens the surface for formation of the hip joint. At the lower part of the acetabulum is the acetabular notch, which is continuous with a circular depression, the acetabular fossa, at the bottom of the cavity of the acetabulum. The rest of the acetabulum is formed by a curved, crescent-moon shaped surface, the lunate surface, where the joint is made with the head of the femur. Its counterpart in the pectoral girdle is the glenoid fossa.
In reptiles and in birds, the acetabula are deep sockets.
# Etymology
The word acetabulum means "little vinegar cup", and was the Latin word for a small vessel for storing vinegar (see acetabulum). The word was later also used as a unit of volume, equal to roughly 270 ml.
# Additional images
- Right hip bone. External surface.
- Plan of ossification of the hip bone.
- Symphysis pubis exposed by a coronal section.
- Left hip-joint, opened by removing the floor of the acetabulum from within the pelvis.
- Hip-joint, front view.
- Capsule of hip-joint (distended). Posterior aspect.
- Structures surrounding right hip-joint.
# External links
- Template:SUNYAnatomyLabs - "Major Joints of the Lower Extremity: Hip joint"
- Template:SUNYAnatomyLabs - "The Female Pelvis: Articulated bones of pelvis"
Template:Gray's
Template:Pelvis
cs:Acetabulum
de:Hüftgelenk#Anatomie
it:Cotile
nl:Acetabulum
fi:Lonkkamalja
sv:Höftledsgrop
tl:Acetabulum
uk:Вертлюжна западина
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Acetabulum | |
0c7bfc907d921a4012ffd34fe644f70e2475944d | wikidoc | Acetyl-CoA | Acetyl-CoA
Acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main use is to convey the carbon atoms within the acetyl group to the Krebs Cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester between coenzyme A (a thiol) and acetic acid (an acyl group carrier). Acetyl-CoA is produced during the second step of aerobic cellular respiration, pyruvate decarboxylation, which occurs in the matrix of the mitochondria. Acetyl-CoA then enters Krebs Cycle.
Acetyl-CoA is also an important component in the biogenic synthesis of the neurotransmitter acetylcholine. Choline, in combination with Acetyl-CoA, is catalyzed by the enzyme choline acetyltransferase to produce acetylcholine and a coenzyme a byproduct.
# Functions
## Pyruvate dehydrogenase and pyruvate formate lyase reactions
The oxidative conversion of pyruvate into acetyl-CoA is referred to as the pyruvate dehydrogenase reaction. It is catalyzed by the pyruvate dehydrogenase complex. Other conversions between pyruvate and acetyl-CoA are possible. For example, pyruvate formate lyase disproportionates pyruvate into acetyl-CoA and formic acid. The pyruvate formate lyase reaction does not involve any net oxidation or reduction.
## Fatty acid metabolism
In animals, acetyl-CoA is very central to the balance between carbohydrate metabolism and fat metabolism (see fatty acid synthesis). In normal circumstances, acetyl-CoA from fatty acid metabolism feeds into Krebs Cycle, contributing to the cell's energy supply. In the liver, when levels of circulating fatty acids are high, the production of acetyl-CoA from fat breakdown exceeds the cellular energy requirements. To make use of the energy available from the excess acetyl-CoA, ketone bodies are produced which can then circulate in the blood.
In some circumstances, this can lead to the presence of ketone bodies in the blood, a condition called ketosis. Benign dietary ketosis can safely occur in people following low-carbohydrate diets, which cause fats to be metabolised as a major source of energy. This is different from ketosis brought on as a result of starvation and ketoacidosis, a dangerous condition that can affect diabetics.
In plants, de novo fatty acid synthesis occurs in the plastids. Many seeds accumulate large resevoirs of seed oils to support germination and early growth of the seedling before it is a net photosynthetic organism. Fatty acids are incorporated into membrane lipids, the major component of most membranes.
## Other reactions
- Acetyl-CoA is the precursor to HMG-CoA, which, in animals, is a vital component in cholesterol and ketone synthesis. Furthermore, it contributes an acetyl group to choline to produce acetylcholine, in a reaction catalysed by choline acetyltransferase.
- In plants and animals, cytosolic acetyl-CoA is synthesized by ATP citrate lyase . When glucose is abundant in the blood of animals, it is converted via glycolysis in the cytosol to pyruvate, and thence to acetyl-CoA in the mitochondrion. The excess of acetyl-CoA results in production of excess citrate, which is exported into the cytosol to give rise to cytosolic acetyl-CoA.
- Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to malonyl-CoA, a substrate required for synthesis of flavonones and related polyketides, for elongation of fatty acids to produce waxes, cuticle, and seed oils in members of the Brassica family, and for malonation of proteins and other phytochemicals .
- Two acetyl-CoA can be condensed to create acetoacetyl-CoA, the first step in the HMG-CoA/ mevalonic acid pathway leading to synthesis of isoprenoids. In plants, these include sesquiterpenes, brassinosteroids (hormones), and membrane sterols. | Acetyl-CoA
Template:Chembox new
Acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main use is to convey the carbon atoms within the acetyl group to the Krebs Cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester between coenzyme A (a thiol) and acetic acid (an acyl group carrier). Acetyl-CoA is produced during the second step of aerobic cellular respiration, pyruvate decarboxylation, which occurs in the matrix of the mitochondria. Acetyl-CoA then enters Krebs Cycle.
Acetyl-CoA is also an important component in the biogenic synthesis of the neurotransmitter acetylcholine. Choline, in combination with Acetyl-CoA, is catalyzed by the enzyme choline acetyltransferase to produce acetylcholine and a coenzyme a byproduct.
# Functions
## Pyruvate dehydrogenase and pyruvate formate lyase reactions
The oxidative conversion of pyruvate into acetyl-CoA is referred to as the pyruvate dehydrogenase reaction. It is catalyzed by the pyruvate dehydrogenase complex. Other conversions between pyruvate and acetyl-CoA are possible. For example, pyruvate formate lyase disproportionates pyruvate into acetyl-CoA and formic acid. The pyruvate formate lyase reaction does not involve any net oxidation or reduction.
## Fatty acid metabolism
In animals, acetyl-CoA is very central to the balance between carbohydrate metabolism and fat metabolism (see fatty acid synthesis). In normal circumstances, acetyl-CoA from fatty acid metabolism feeds into Krebs Cycle, contributing to the cell's energy supply. In the liver, when levels of circulating fatty acids are high, the production of acetyl-CoA from fat breakdown exceeds the cellular energy requirements. To make use of the energy available from the excess acetyl-CoA, ketone bodies are produced which can then circulate in the blood.
In some circumstances, this can lead to the presence of ketone bodies in the blood, a condition called ketosis. Benign dietary ketosis can safely occur in people following low-carbohydrate diets, which cause fats to be metabolised as a major source of energy. This is different from ketosis brought on as a result of starvation and ketoacidosis, a dangerous condition that can affect diabetics.
In plants, de novo fatty acid synthesis occurs in the plastids. Many seeds accumulate large resevoirs of seed oils to support germination and early growth of the seedling before it is a net photosynthetic organism. Fatty acids are incorporated into membrane lipids, the major component of most membranes.
## Other reactions
- Acetyl-CoA is the precursor to HMG-CoA, which, in animals, is a vital component in cholesterol and ketone synthesis. Furthermore, it contributes an acetyl group to choline to produce acetylcholine, in a reaction catalysed by choline acetyltransferase.
- In plants and animals, cytosolic acetyl-CoA is synthesized by ATP citrate lyase [1]. When glucose is abundant in the blood of animals, it is converted via glycolysis in the cytosol to pyruvate, and thence to acetyl-CoA in the mitochondrion. The excess of acetyl-CoA results in production of excess citrate, which is exported into the cytosol to give rise to cytosolic acetyl-CoA.
- Acetyl-CoA can be carboxylated in the cytosol by acetyl-CoA carboxylase, giving rise to malonyl-CoA, a substrate required for synthesis of flavonones and related polyketides, for elongation of fatty acids to produce waxes, cuticle, and seed oils in members of the Brassica family, and for malonation of proteins and other phytochemicals [2].
- Two acetyl-CoA can be condensed to create acetoacetyl-CoA, the first step in the HMG-CoA/ mevalonic acid pathway leading to synthesis of isoprenoids. In plants, these include sesquiterpenes, brassinosteroids (hormones), and membrane sterols. | https://www.wikidoc.org/index.php/Acetyl-CoA | |
93fd4ca4b590b4a0be6dd42e22e373688a3747f2 | wikidoc | Arthralgia | Arthralgia
# Overview
Arthralgia (from Greek arthro-, joint + -algos, pain) literally means joint pain; it is a symptom of injury, infection, illnesses in particular arthritis or an allergic reaction to medication.
According to MeSH, the term arthralgia should only be used when the condition is non-inflammatory, and the term arthritis should be used when the condition is inflammatory.
# Causes
The causes of arthralgia are varied and range from, a joints perspective, degenerative and destructive processes such as osteoarthritis and sports injuries to inflammation of tissues surrounding the joints (e.g. bursitis, a painful inflammation of bursa, fluid filled sacks around the joints).
## Common Causes
- Behcet's disease
- Chikungunya virus
- Crohn's disease
- Dengue fever
- Gout
- Osteoarthritis
- Rheumatoid arthritis
- Rheumatic fever
- Ross river virus
- Lupus erythematosus
- Tenosynovitis
- Ulcerative colitis
- Medication like terconazole
## Causes by Organ System
## Causes in Alphabetical Order
# Diagnosis
## History and Symptoms
Diagnosis involves interviewing the patient and performing physical exams. When attempting to establish the cause of the arthralgia, the emphasis is on the interview. The patient is asked questions intended to narrow the number of potential causes. Given the varied nature of these possible causes, the questions may strike the uninitiated as irrelevant. For example the patient may be asked about dry mouth, light sensitivity, rashes or a history of seizures.
Answering yes or no to any of these questions limits the number of possible causes and guides the doctor toward the appropriate exams and lab tests.
# Treatment
## Medical Therapy
Treatment depends on specific underlying cause. The underlying cause will be treated first and foremost. The treatments may include immunosuppressants for immune system dysfunction, antibiotics when an infection is the cause, and discontinuing medication when an allergic reaction is the cause. When treating the primary cause, pain management may still play a role in treatment. The extent of its role varies depending on the specific cause of the arthralgia. Pain management may include stretching exercises, over the counter pain medications, prescription pain medication, or other treatments deemed appropriate for the symptoms.
## Surgery
Joint replacement surgery is done for severely damaged joints. | Arthralgia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].
# Overview
Arthralgia (from Greek arthro-, joint + -algos, pain) literally means joint pain; [1][2] it is a symptom of injury, infection, illnesses in particular arthritis or an allergic reaction to medication.[3]
According to MeSH, the term arthralgia should only be used when the condition is non-inflammatory, and the term arthritis should be used when the condition is inflammatory.[4]
# Causes
The causes of arthralgia are varied and range from, a joints perspective, degenerative and destructive processes such as osteoarthritis and sports injuries to inflammation of tissues surrounding the joints (e.g. bursitis, a painful inflammation of bursa, fluid filled sacks around the joints). [5]
## Common Causes
- Behcet's disease
- Chikungunya virus
- Crohn's disease
- Dengue fever
- Gout
- Osteoarthritis
- Rheumatoid arthritis
- Rheumatic fever
- Ross river virus
- Lupus erythematosus
- Tenosynovitis
- Ulcerative colitis
- Medication like terconazole
## Causes by Organ System
## Causes in Alphabetical Order[6][7]
# Diagnosis
## History and Symptoms
Diagnosis involves interviewing the patient and performing physical exams. When attempting to establish the cause of the arthralgia, the emphasis is on the interview.[2] The patient is asked questions intended to narrow the number of potential causes. Given the varied nature of these possible causes, the questions may strike the uninitiated as irrelevant. For example the patient may be asked about dry mouth, light sensitivity, rashes or a history of seizures.[2] [8]
Answering yes or no to any of these questions limits the number of possible causes and guides the doctor toward the appropriate exams and lab tests.
# Treatment
## Medical Therapy
Treatment depends on specific underlying cause. The underlying cause will be treated first and foremost. The treatments may include immunosuppressants for immune system dysfunction, antibiotics when an infection is the cause, and discontinuing medication when an allergic reaction is the cause. When treating the primary cause, pain management may still play a role in treatment. The extent of its role varies depending on the specific cause of the arthralgia. Pain management may include stretching exercises, over the counter pain medications, prescription pain medication, or other treatments deemed appropriate for the symptoms.
## Surgery
Joint replacement surgery is done for severely damaged joints. | https://www.wikidoc.org/index.php/Aching_joints | |
f4fcaf1060ad7b2ad4b697c85b6b257ef84c7386 | wikidoc | Aclidinium | Aclidinium
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Aclidinium is an antimuscarinic and bronchodilator that is FDA approved for the treatment of long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.. Common adverse reactions include headache, cough, and nasopharyngitis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.
- Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aclidinium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aclidinium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Aclidinium FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aclidinium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aclidinium in pediatric patients.
# Contraindications
None.
# Warnings
### Not for Acute Use
Aclidinium bromide is intended as a twice-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).
### Paradoxical Bronchospasm
Inhaled medicines, including Aclidinium bromide, may cause paradoxical bronchospasm. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.
### Worsening of Narrow-Angle Glaucoma
Aclidinium bromide should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
### Worsening of Urinary Retention
Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
### Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### 3-Month and 6-Month Trials
- Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.
- The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.
TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.
In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were diabetes mellitus, dry mouth, 1st degree AV block, osteoarthritis, cardiac failure, and cardio-respiratory arrest.
### Long-term Safety Trials
Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe COPD. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
## Postmarketing Experience
There is limited information regarding Aclidinium Postmarketing Experience in the drug label.
# Drug Interactions
In vitro studies suggest limited potential for CYP450-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.
### Sympathomimetics, Methylxanthines, Steroids
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of COPD including sympathomimetics (short-acting beta2 agonists), methylxanthines, and oral and inhaled steroids showed no increases in adverse drug reactions.
### Anticholinergics
There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of Aclidinium bromide with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic effects
### Pregnancy Category C
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of organogenesis at approximately 15 times the recommended human daily dose (RHDD) . However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD . Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.
No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD . However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD , and decreased fetal body weights were observed at approximately 2,300 times the RHDD . These fetal findings were observed in the presence of maternal toxicity.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aclidinium in women who are pregnant.
### Labor and Delivery
- The effect of Aclidinium bromide on labor and delivery is unknown.
- Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
### Nursing Mothers
- Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
- Excretion of aclidinium into human milk is probable.
- There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
- Caution should be exercised when Aclidinium bromide is administered to nursing women.
### Pediatric Use
- Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with COPD.
- COPD does not normally occur in children.
- The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.
### Geriatic Use
- Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
- No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
- Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.
### Gender
There is no FDA guidance on the use of Aclidinium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aclidinium with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe renal impairment.
- No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
- Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.
### Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aclidinium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aclidinium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Aclidinium Administration in the drug label.
### Monitoring
There is limited information regarding Aclidinium Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Aclidinium and IV administrations.
# Overdosage
There is limited information regarding Aclidinium overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Aclidinium bromide is a long-acting antimuscarinic agent, which is often referred to as an anticholinergic.
- It has similar affinity to the subtypes of muscarinic receptors M1 to M5.
- In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation.
- The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
- In preclinical in vitro as well as in vivo studies, prevention of acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours.
- The clinical relevance of these findings is unknown.
- The bronchodilation following inhalation of aclidinium bromide is predominantly a site-specific effect.
## Structure
Aclidinium bromide consists of a dry powder formulation of aclidinium bromide for oral inhalation only.
Aclidinium bromide, the active component of TUDORZA PRESSAIR is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-Azoniabicyclooctane, 3--1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:
Aclidinium bromide is a white powder with a molecular formula of C26H30NO4S2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.
Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler. Each actuation of Aclidinium bromide provides a metered dose of 13 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier and 400 mcg of aclidinium bromide. This results in delivery of 375 mcg aclidinium bromide from the mouthpiece, based onin vitro testing at an average flow rate of 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. The PRESSAIR inhaler delivers the target dose at flow rates as low as 35 L/min. Based on a study in adult patients with moderate (N=24) and severe (N=24) COPD the mean peak inspiratory flow (PIF) was 95.3 L/min (range: 54.6 to 129.4 L/min) and 88.7 L/min (range: 72.0 to 106.4 L/min) respectively.
## Pharmacodynamics
### Cardiovascular Effects
- In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of QT interval were observed using QTcF heart-rate correction methods.
- Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr Holter monitoring.
- No clinically significant effects on cardiac rhythm were observed.
## Pharmacokinetics
### Absorption
- The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
- Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.
### Distribution
- Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.
### Metabolism
- Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
- Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
- Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.
### Elimination
- Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
- Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
- Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
- The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
- After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.
### Drug Interactions
- Formal drug interaction studies were not performed.
- In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
- Therefore, it is unlikely that aclidinium bromide causes CYP450 related drug interactions.
The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.
The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.
The effects of hepatic impairment on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
- No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively .
- Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.
- Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day .
# Clinical Studies
### Chronic Obstructive Pulmonary Disease (COPD)=
The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).
### Dose-ranging trial
Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had a forced expiratory volume in one second (FEV1) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough FEV1 and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.
Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with COPD. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.
These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater bronchodilation as measured by change from baseline in morning pre-dose FEV1 at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.
Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.
Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue albuterol during the trial compared to patients treated with placebo.
# How Supplied
Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.
The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
## Storage
Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).
The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.
Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.
Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.
Instruct patients that Aclidinium bromide is a twice daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).
Inform patients that Aclidinium bromide can cause paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
- Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.
Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
# Precautions with Alcohol
Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aclidinium bromide
# Look-Alike Drug Names
There is limited information regarding Aclidinium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Aclidinium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sree Teja Yelamanchili, MBBS [2]
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# Overview
Aclidinium is an antimuscarinic and bronchodilator that is FDA approved for the treatment of long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.. Common adverse reactions include headache, cough, and nasopharyngitis..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.
- Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aclidinium in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aclidinium in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Aclidinium FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Aclidinium in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Aclidinium in pediatric patients.
# Contraindications
None.
# Warnings
### Not for Acute Use
Aclidinium bromide is intended as a twice-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy).
### Paradoxical Bronchospasm
Inhaled medicines, including Aclidinium bromide, may cause paradoxical bronchospasm. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.
### Worsening of Narrow-Angle Glaucoma
Aclidinium bromide should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
### Worsening of Urinary Retention
Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.
### Immediate Hypersensitivity Reactions
Immediate hypersensitivity reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### 3-Month and 6-Month Trials
- Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.
- The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable cardiac disease, narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials.
TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.
In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were diabetes mellitus, dry mouth, 1st degree AV block, osteoarthritis, cardiac failure, and cardio-respiratory arrest.
### Long-term Safety Trials
Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe COPD. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
## Postmarketing Experience
There is limited information regarding Aclidinium Postmarketing Experience in the drug label.
# Drug Interactions
In vitro studies suggest limited potential for CYP450-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.
### Sympathomimetics, Methylxanthines, Steroids
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of COPD including sympathomimetics (short-acting beta2 agonists), methylxanthines, and oral and inhaled steroids showed no increases in adverse drug reactions.
### Anticholinergics
There is a potential for an additive interaction with concomitantly used anticholinergic medications. Therefore, avoid coadministration of Aclidinium bromide with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic effects.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic effects
### Pregnancy Category C
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of organogenesis at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.
No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Aclidinium in women who are pregnant.
### Labor and Delivery
- The effect of Aclidinium bromide on labor and delivery is unknown.
- Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
### Nursing Mothers
- Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
- Excretion of aclidinium into human milk is probable.
- There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
- Caution should be exercised when Aclidinium bromide is administered to nursing women.
### Pediatric Use
- Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with COPD.
- COPD does not normally occur in children.
- The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.
### Geriatic Use
- Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
- No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
- Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.
### Gender
There is no FDA guidance on the use of Aclidinium with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Aclidinium with respect to specific racial populations.
### Renal Impairment
- The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe renal impairment.
- No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
- Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.
### Hepatic Impairment
The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Aclidinium in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Aclidinium in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Aclidinium Administration in the drug label.
### Monitoring
There is limited information regarding Aclidinium Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Aclidinium and IV administrations.
# Overdosage
There is limited information regarding Aclidinium overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Aclidinium bromide is a long-acting antimuscarinic agent, which is often referred to as an anticholinergic.
- It has similar affinity to the subtypes of muscarinic receptors M1 to M5.
- In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to bronchodilation.
- The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
- In preclinical in vitro as well as in vivo studies, prevention of acetylcholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours.
- The clinical relevance of these findings is unknown.
- The bronchodilation following inhalation of aclidinium bromide is predominantly a site-specific effect.
## Structure
Aclidinium bromide consists of a dry powder formulation of aclidinium bromide for oral inhalation only.
Aclidinium bromide, the active component of TUDORZA PRESSAIR is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-Azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:
Aclidinium bromide is a white powder with a molecular formula of C26H30NO4S2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.
Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler. Each actuation of Aclidinium bromide provides a metered dose of 13 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier and 400 mcg of aclidinium bromide. This results in delivery of 375 mcg aclidinium bromide from the mouthpiece, based onin vitro testing at an average flow rate of 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. The PRESSAIR inhaler delivers the target dose at flow rates as low as 35 L/min. Based on a study in adult patients with moderate (N=24) and severe (N=24) COPD the mean peak inspiratory flow (PIF) was 95.3 L/min (range: 54.6 to 129.4 L/min) and 88.7 L/min (range: 72.0 to 106.4 L/min) respectively.
## Pharmacodynamics
### Cardiovascular Effects
- In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of QT interval were observed using QTcF heart-rate correction methods.
- Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr Holter monitoring.
- No clinically significant effects on cardiac rhythm were observed.
## Pharmacokinetics
### Absorption
- The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
- Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.
### Distribution
- Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.
### Metabolism
- Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
- Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
- Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.
### Elimination
- Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
- Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
- Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
- The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
- After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.
### Drug Interactions
- Formal drug interaction studies were not performed.
- In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
- Therefore, it is unlikely that aclidinium bromide causes CYP450 related drug interactions.
The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.
The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe renal impairment. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.
The effects of hepatic impairment on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
- No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].
- Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.
- Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].
# Clinical Studies
### Chronic Obstructive Pulmonary Disease (COPD)=
The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).
### Dose-ranging trial
Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had a forced expiratory volume in one second (FEV1) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced vital capacity (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough FEV1 and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.
Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with COPD. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.
These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater bronchodilation as measured by change from baseline in morning pre-dose FEV1 at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.
Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.
Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue albuterol during the trial compared to patients treated with placebo.
# How Supplied
Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.
The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
## Storage
Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].
The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.
Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.
Keep out of reach of children.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.
Instruct patients that Aclidinium bromide is a twice daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).
Inform patients that Aclidinium bromide can cause paradoxical bronchospasm. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.
Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
- Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.
Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
# Precautions with Alcohol
Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Aclidinium bromide
# Look-Alike Drug Names
There is limited information regarding Aclidinium Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Aclidinium | |
6805e911999c84d3a2a185b182654fcbdd049adf | wikidoc | Argatroban | Argatroban
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# Overview
Argatroban is a direct thrombin inhibitor that is FDA approved for the {{{indicationType}}} of thrombosis in heparin-induced thrombocytopenia and prophylaxis in PCI. Common adverse reactions include dyspnea, hypotension, fever, diarrhea, chest pain, back pain, nausea, vomiting, headache, sepsis, and cardiac arrest.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Before administering argatroban, discontinue heparin therapy and obtain a baseline aPTT.
- Dosing Information
- Initial dose: 2 mcg/kg/min (continuous infusion)
- After the initiation of argatroban injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range
- Initial dose: 25 mcg/kg/min , administer a bolus of 350 mcg/kg via a large bore IV line over 3 to 5 minutes.
- Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed.
- The PCI procedure may proceed if the ACT is greater than 300 seconds.
- If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later
- If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later.
- Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Argatroban in adult patients.
### Non–Guideline-Supported Use
### Cardiovascular surgical procedure
- Dosing Information
- Continuous infusion of 0.3 to 0.96 mcg/kg/min
- There are limited studies that suggest its usefulness.
### Cerebral thrombosis
- Dosing Information
- Initial dose: 60 mg/day as a continuous IV infusion for 2 days
- Maintenance dose: 10 mg twice daily for 5 days
### Disseminated intravascular coagulation
- Dosing Information
- 0.7 mcg/kg/min
### Extracorporeal circulation procedure
- Dosing Information
- 2 mcg/kg/min
### Prophylaxis in Hemodialysis for Venous Catheter Occlusion
- As an alternative to heparin.
### Myocardial Infarction
- Dosing Information
- Initial dose: 100 mcg/kg IV bolus
- Maintenance dose: 3 mcg/kg IV infusion
### Unstable Angina
- Dosing Information
- 0.5 to 5 mcg/kg/min over 4 hours
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Initial dose: 0.75 mcg/kg/min
- Check the aPTT two hours after the initiation of the argatroban infusion and adjust the dose to achieve the target aPTT.
- Increments of 0.1 to 0.25 mcg/kg/min for pediatric patients with normal hepatic function may be considered.
- Increments of 0.05 mcg/kg/min or lower for pediatric patients with impaired hepatic function may be considered.
- Initiate the infusion at a dose of 0.2 mcg/kg/min among seriously ill pediatric patients with impaired hepatic function
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Argatroban in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Argatroban in pediatric patients.
# Contraindications
- Patients with major bleeding.
- Patients with a history of hypersensitivity to argatroban. (Airway, skin, and generalized hypersensitivity reactions have been reported)
# Warnings
### Risk of Hemorrhage
- Hemorrhage can occur at any site in the body in patients receiving argatroban.
- Unexplained fall in hematocrit or blood pressure may indicate hemorrhage.
- Intracranial and retroperitoneal hemorrahage have been reported.
- The risk of hemorrahage with argatroban may be increased in severe hypertension; immediately following lumbar puncture, spinal anesthesia, major surgery (especially involving the brain, spinal cord, or eye), hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders, and gastrointestinal lesions such as ulcerations.
- Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.
### Use in Hepatic Impairment
- When administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved.
- Achievement of steady state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.
- Also, upon cessation of argatroban infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of argatroban.
- Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal.
### Laboratory Tests
- Anticoagulation effects associated with argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT).
- Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by argatroban, the therapeutic ranges for these tests have not been identified for argatroban therapy.
- In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring argatroban anticoagulant activity during the procedure.
- The concomitant use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### Adverse Events in Patients with HIT (With or Without Thrombosis)
The following safety information is based on all 568 patients treated with argatroban in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events.
Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥2 g/dL, that led to a transfusion of ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding.
Table 4 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis).
Table 5 gives an overview of the most frequently observed non-hemorrhagic events sorted by decreasing frequency of occurrence (=2%) among argatroban-treated HIT/HITTS patients.
### Adverse Events in Patients with or at Risk for HIT Patients Undergoing PCI
The following safety information is based on 91 patients initially treated with argatroban and 21 patients subsequently re-exposed to argatroban for a total of 112 PCIs with argatroban anticoagulation. Adverse events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) events.
Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥5 g/dL, that led to transfusion of ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint.
The rate of major bleeding events in patients treated with argatroban in the PCI trials was 1.8%.
Table 7 gives an overview of the most frequently observed non-hemorrhagic events (>2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients.
There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatroban-treated-patients with or at risk for HIT undergoing PCI.
### Intracranial Bleeding In Other Populations
Increased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses. In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis.
The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively.
### Allergic Reactions
One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media.
Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order or frequency):
- Airway reactions (coughing, dyspnea): 10% or more
- Skin reactions (rash, bullous eruption): 1 to <10%
- General reactions (vasodilation): 1 to 10%
Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients.
## Postmarketing Experience
There is limited information regarding Argatroban Postmarketing Experience in the drug label.
# Drug Interactions
### Heparin
- If argatroban is to be initiated after cessation of heparin therapy, allow sufficient time for heparin’s effect on the aPTT to decrease prior to initiation of argatroban therapy.
### Oral Anticoagulant Agents
- Pharmacokinetic drug-drug interactions between argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated.
- However, the concomitant use of argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR).
### Aspirin/ Acetaminophen
- No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen.
### Thrombolytic Agents
- The safety and effectiveness of argatroban with thrombolytic agents have not been established.
### Glycoprotein IIb/IIIa Antagonists
- The safety and effectiveness of argatroban with glycoprotein IIb/IIIa antagonists have not been established.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies of argatroban use in pregnant women. Developmental studies performed in rats with argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Argatroban in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Argatroban during labor and delivery.
### Nursing Mothers
It is not known whether argatroban is excreted in human milk. Argatroban is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from argatroban, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were <6 months, n = 8; six months to <8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions and were receiving multiple concomitant medications. Thirteen patients received argatroban solely as a continuous infusion (no bolus dose). Dosing was initiated in the majority of these 13 patients at 1 mcg/kg/min. Dosing was titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during argatroban administration to two patients and following argatroban discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of argatroban therapy in the setting of sepsis and thrombocytopenia. Another patient completed 14 days of argatroban treatment in the study, but experienced an intracranial hemorrhage while receiving argatroban following completion of the study treatment period.
### Geriatic Use
Of the total number of subjects (1340) in clinical studies of argatroban, 35% were 65 and over. In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients had increased underlying conditions, which may predispose them to events. The studies were not sized appropriately to detect differences in safety between age groups.
### Gender
There are no clinically significant effects of gender on the pharmacokinetics or pharmacodynamics (e.g., aPTT) of argatroban in adults.
### Race
There is no FDA guidance on the use of Argatroban with respect to specific racial populations.
### Renal Impairment
No dosage adjustment is necessary in patients with renal dysfunction. The effect of renal disease on the pharmacokinetics of argatroban was studied in 6 subjects with normal renal function (mean Clcr = 95 ± 16 mL/min) and in 18 subjects with mild (mean Clcr = 64 ± 10 mL/min), moderate (mean Clcr = 41 ± 5.8 mL/min), and severe (mean Clcr = 5 ± 7 mL/min) renal impairment. The pharmacokinetics and pharmacodynamics of argatroban at dosages up to 5 mcg/kg/min were not significantly affected by renal dysfunction.
Use of argatroban was evaluated in a study of 12 patients with stable end-stage renal disease undergoing chronic intermittent hemodialysis. Argatroban was administered at a rate of 2 to 3 mcg/kg/min (begun at least 4 hours prior to dialysis) or as a bolus dose of 250 mcg/kg at the start of dialysis followed by a continuous infusion of 2 mcg/kg/min. Although these regimens did not achieve the goal of maintaining ACT values at 1.8 times the baseline value throughout most of the hemodialysis period, the hemodialysis sessions were successfully completed with both of these regimens. The mean ACTs produced in this study ranged from 1.39 to 1.82 times baseline, and the mean aPTTs ranged from 1.96 to 3.4 times the baseline. When argatroban was administered as a continuous infusion of 2 mcg/kg/min prior to and during a 4-hour hemodialysis session, approximately 20% was cleared through dialysis.
### Hepatic Impairment
Dose reduction and careful titration are required when administering argatroban to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population. Patients with hepatic impairment were not studied in percutaneous coronary intervention (PCI) trials. At a dose of 2.5 mcg/kg/min, hepatic impairment is associated with decreased clearance and increased elimination half-life of argatroban (to 1.9 mL/kg/min and 181 minutes, respectively, for patients with a Child-Pugh score greater than 6).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Argatroban in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Argatroban in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Argatroban should not be mixed with other drugs prior to dilution.
Argatroban should be diluted in 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to a final concentration of 1 mg/mL. The contents of each 2.5-mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent.
The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. Use of diluent at room temperature is recommended. The final solution must be clear before use. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5. Prepared solutions should not be exposed to direct sunlight. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
### Conversion to Oral Anticoagulant Therapy
- When converting patients from argatroban to oral anticoagulant therapy, consider the potential for combined effects on INR with co-administration of argatroban and warfarin.
- A loading dose of warfarin should not be used. Initiate therapy using the expected daily dose of warfarin.
- To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that argatroban and warfarin therapy be overlapped.
- There are insufficient data available to recommend the duration of the overlap.
- Measure INR daily while argatroban Injection and warfarin are co-administered. In general, with doses of argatroban injection up to 2 mcg/kg/min, argatroban injection can be discontinued when the INR is >4 on combined therapy.
- After argatroban injection is discontinued, repeat the INR measurement in 4 to 6 hours.
- If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.
- For doses greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban is less predictable.
- In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of argatroban injection to a dose of 2 mcg/kg/min.
- Repeat the INR on argatroban injection and warfarin 4 to 6 hours after reduction of the argatroban Injection dose and follow the process outlined above for administering argatroban injection at doses up to 2 mcg/kg/min.
### Monitoring
For use in HIT, therapy with argatroban injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of argatroban injection.
Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.
For use in PCI, therapy with argatroban injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure. Obtain additional ACTs every 20 to 30 minutes during prolonged procedure.
In general, therapy with argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of argatroban in patients without hepatic impairment. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.
# IV Compatibility
There is limited information regarding the compatibility of Argatroban and IV administrations.
# Overdosage
- Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing argatroban or by decreasing the argatroban dose.
- In clinical studies, anticoagulation parameters generally returned from therapeutic levels to baseline within 2 to 4 hours after discontinuation of the drug.
- Reversal of anticoagulant effect may take longer in patients with hepatic impairment.
- No specific antidote to argatroban is available; if life-threatening bleeding occurs and excessive plasma levels of argatroban are suspected, discontinue argatroban immediately and measure aPTT and other coagulation parameters.
- When argatroban was administered as a continuous infusion (2 mcg/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of argatroban was cleared through dialysis.
- Single intravenous doses of argatroban at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively.
- The symptoms of acute toxicity were loss of lighting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.
# Pharmacology
## Mechanism of Action
Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.
Argatroban inhibits thrombin with an inhibition constant (Ki) of 0.04 μM. At therapeutic concentrations, argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein).
Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.
## Structure
Argatroban is a synthetic direct thrombin inhibitor and the chemical name is 1--1-oxo-2-(1,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.
The molecular formula of Argatroban is C23H36N6O5SH2O. Its molecular weight is 526.66 g/mol. The structural formula is shown below:
Argatroban is a white, odorless crystalline powder that is freely soluble in glacial acetic acid, slightly soluble in ethanol, and insoluble in acetone, ethyl acetate, and ether. Argatroban injection is a sterile clear, colorless to pale yellow, slightly viscous solution. Argatroban is available in 250-mg (in 2.5-mL) single-use amber vials, with white flip-top caps. Each mL of sterile, nonpyrogenic solution contains 100 mg Argatroban. Inert ingredients: 1300 mg Propylene glycol, 800 mg Dehydrated alcohol.
## Pharmacodynamics
When argatroban is administered by continuous infusion, anticoagulant effects and plasma concentrations of argatroban follow similar, predictable temporal response profiles, with low intersubject variability. Immediately upon initiation of argatroban infusion, anticoagulant effects are produced as plasma argatroban concentrations begin to rise. Steady-state levels of both drug and anticoagulant effect are typically attained within 1 to 3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state plasma argatroban concentrations increase proportionally with dose (for infusion doses up to 40 mcg/kg/min in healthy subjects) and are well correlated with steady-state anticoagulant effects. For infusion doses up to 40 mcg/kg/min, argatroban increases in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the prothrombin time (PT), the International Normalized Ratio (INR), and the thrombin time (TT) in healthy volunteers and cardiac patients. Representative steady-state plasma argatroban concentrations and anticoagulant effects are shown below for argatroban infusion doses up to 10 mcg/kg/min.
Effect on International Normalized Ratio (INR): Because argatroban is a direct thrombin inhibitor, co-administration of argatroban and warfarin produces a combined effect on the laboratory measurement of the INR. However, concurrent therapy, compared to warfarin monotherapy, exerts no additional effect on vitamin K–dependent factor Xa activity.
The relationship between INR on co-therapy and warfarin alone is dependent on both the dose of argatroban and the thromboplastin reagent used. This relationship is influenced by the International Sensitivity Index (ISI) of the thromboplastin. Data for 2 commonly utilized thromboplastins with ISI values of 0.88 (Innovin, Dade) and 1.78 (Thromboplastin C Plus, Dade) are presented in Figure 2 for an argatroban dose of 2 mcg/kg/min. Thromboplastins with higher ISI values than shown result in higher INRs on combined therapy of warfarin and argatroban. These data are based on results obtained in normal individuals.
The graph above demonstrates the relationship between INR for warfarin alone and INR for warfarin co-administered with argatroban at a dose of 2 mcg/kg/min. To calculate INR for warfarin alone (INRW), based on INR for co-therapy of warfarin and argatroban (INRWA), when the argatroban dose is 2 mcg/kg/min, use the equation next to the appropriate curve. Example: At a dose of 2 mcg/kg/min and an INR performed with Thromboplastin A, the equation 0.19 + 0.57 (INRWA) = INRW would allow a prediction of the INR on warfarin alone (INRW). Thus, using an INRWA value of 4.0 obtained on combined therapy: INRW = 0.19 + 0.57 (4) = 2.47 as the value for INR on warfarin alone. The error (confidence interval) associated with a prediction is ± 0.4 units. Similar linear relationships and prediction errors exist for argatroban at a dose of 1 mcg/kg/min. Thus, for argatroban doses of 1 or 2 mcg/kg/min, INRW can be predicted from INRWA. For argatroban doses greater than 2 mcg/kg/min, the error associated with predicting INRW from INRWA is ± 1. Thus, INRW cannot be reliably predicted from INRWA at doses greater than 2 mcg/kg/min.
## Pharmacokinetics
### Distribution
Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent steady-state volume of distribution of 174 mL/kg (12.18 L in a 70-kg adult). Argatroban is 54% bound to human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34%, respectively.
### Metabolism
The main route of argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of each of the 4 known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. The primary metabolite (M1) exerts 3- to 5-fold weaker anticoagulant effects than argatroban. Unchanged argatroban is the major component in plasma. The plasma concentrations of M1 range between 0% and 20% of that of the parent drug. The other metabolites (M2 to M4) are found only in very low quantities in the urine and have not been detected in plasma or feces. These data, together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not an important elimination pathway in vivo.
Total body clearance is approximately 5.1 mL/kg/min (0.31 L/kg/hr) for infusion doses up to 40 mcg/kg/min. The terminal elimination half-life of argatroban ranges between 39 and 51 minutes.
There is no interconversion of the 21–(R):21–(S) diastereoisomers. The plasma ratio of these diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at 65:35 (± 2%).
### Excretion
Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which 14C-argatroban (5 mcg/kg/min) was infused for 4 hours into healthy subjects, approximately 65% of the radioactivity was recovered in the feces within 6 days of the start of infusion with little or no radioactivity subsequently detected. Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start of infusion. Little or no additional urinary radioactivity was subsequently detected. Average percent recovery of unchanged drug, relative to total dose, was 16% in urine and at least 14% in feces.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with argatroban have not been performed.
Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte, and WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests, or the mouse micronucleus test.
Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.
# Clinical Studies
### Heparin-Induced Thrombocytopenia
The safety and efficacy of argatroban were evaluated in a historically controlled efficacy and safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These studies were comparable with regard to study design, study objectives, dosing regimens as well as study outline, conduct, and monitoring. In these studies, 568 adult patients were treated with argatroban and 193 adult patients made up the historical control group. Patients had a clinical diagnosis of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with thrombosis (HITTS heparin-induced thrombocytopenia and thrombosis syndrome) and were males or non-pregnant females between the age of 18 and 80 years old. HIT/HITTS was defined by a fall in platelet count to less than 100,000/μL or a 50% decrease in platelets after the initiation of heparin therapy with no apparent explanation other than HIT. Patients with HITTS also had an arterial or venous thrombosis documented by appropriate imaging techniques or supported by clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism, or other clinical indications of vascular occlusion. Patients who had documented histories of positive heparin-dependent antibody tests without current thrombocytopenia or heparin challenge (e.g., patients with latent disease) were also included if they required anticoagulation.
These studies did not include patients with documented unexplained aPTT >200% of control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HIT, a lumbar puncture within the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or a thrombotic stroke within the past 6 months unrelated to HIT.
The initial dose of argatroban was 2 mcg/kg/min. Two hours after the start of the argatroban infusion, an aPTT level was obtained and dose adjustments were made (up to a maximum of 10 mcg/kg/min) to achieve a steady-state aPTT value that was 1.5 to 3.0 times the baseline value, not to exceed 100 seconds. Overall the mean aPTT level for HIT and HITTS patients during the argatroban infusion increased from baseline values of 34 and 38 seconds, respectively, to 62.5 and 64.5 seconds, respectively.
The primary efficacy analysis was based on a comparison of event rates for a composite endpoint that included death (all causes), amputation (all causes) or new thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary analyses included evaluation of the event rates for the components of the composite endpoint as well as time-to-event analyses.
In Study 1, a total of 304 patients were enrolled as follows: active HIT (n = 129), active HITTS (n =144), or latent disease (n = 31). Among the 193 historical controls, 139 (72%) had active HIT, 46 (24%) had active HITTS, and 8 (4%) had latent disease. Within each group, those with active HIT and those with latent disease were analyzed together. Positive laboratory confirmation of HIT/HITTS by the heparin-induced platelet aggregation test or serotonin release assay was demonstrated in 174 of 304 (57%) argatroban-treated patients (i.e., in 80 with HIT or latent disease and 94 with HITTS) and in 149 of 193 (77%) historical controls (i.e., in 119 with HIT or latent disease and 30 with HITTS). The test results for the remainder of the patients and controls were either negative or not determined.
There was a significant improvement in the composite outcome in patients with HIT and HITTS treated with argatroban versus those in the historical control group (see Table 9). The components of the composite endpoint are shown in Table 9.
Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of argatroban by these analyses.
A time-to-event analysis for the composite endpoint is shown in Figure 3 for patients with HIT and Figure 4 for patients with HITTS.
In Study 2, a total of 264 patients were enrolled as follows: HIT (n = 125) or HITTS (n = 139). There was a significant improvement in the composite efficacy outcome for argatroban-treated patients, versus the same historical control group from Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS (41.0% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43.0%). Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of argatroban.
In Study 1, the mean (± SE) dose of argatroban administered was 2.0 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and 81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater than the baseline aPTT at the first assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS) following initiation of argatroban therapy.
No enhancement of aPTT response was observed in subjects receiving repeated administration of argatroban.
In Study 1, 53% of patients with HIT and 58% of patients with HITTS, had a recovery of platelet count by Day 3. Platelet Count Recovery was defined as an increase in platelet count to >100,000/μL or to at least 1.5-fold greater than the baseline count (platelet count at study initiation) by Day 3 of the study.
### Percutaneous Coronary Intervention (PCI) Patients with or at Risk for HIT
In 3 similarly designed trials, argatroban was administered to 91 patients with current or previous clinical diagnosis of HIT or heparin-dependent antibodies, who underwent a total of 112 percutaneous coronary interventions (PCIs) including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, or atherectomy. Among the 91 patients undergoing their first PCI with argatroban, notable ongoing or recent medical history included myocardial infarction (n = 35), unstable angina (n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The average age was 67.6 years (median 70.7, range 44 to 86), and the average weight was 82.5 kg (median 81.0 kg, range 49 to 141).
Twenty-one of the 91 patients had a repeat PCI using argatroban an average of 150 days after their initial PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were assessed against historical control populations who had been anticoagulated with heparin.
All patients received oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After venous or arterial sheaths were in place, anticoagulation was initiated with a bolus of argatroban of 350 mcg/kg via a large-bore intravenous line or through the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion of 25 mcg/kg/min was initiated to achieve a therapeutic activated clotting time (ACT) of 300 to 450 seconds. If necessary to achieve this therapeutic range, the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose of 150 mcg/kg could be given. Each patient’s ACT was checked 5 to 10 minutes following the bolus dose. The ACT was checked as clinically indicated. Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation of argatroban and when the ACT was less than 160 seconds.
If a patient required anticoagulation after the procedure, argatroban could be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours after this dose reduction and the dose of argatroban then was adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5 and 3 times baseline value (not to exceed 100 seconds).
In 92 of the 112 interventions (82%), the patient received the initial bolus of 350 mcg/kg and an initial infusion dose of 25 mcg/kg/min. The majority of patients did not require additional bolus dosing during the PCI procedure. The mean value for the initial ACT measurement after the start of dosing for all interventions was 379 sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value per intervention over all measurements taken during the procedure was 416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About 65% of patients had ACTs within the recommended range of 300 to 450 seconds throughout the procedure. The investigators did not achieve anticoagulation within the recommended range in about 23% of patients. However, in this small sample, patients with ACTs below 300 seconds did not have more coronary thrombotic events, and patients with ACTs over 450 seconds did not have higher bleeding rates.
Acute procedural success was defined as lack of death, emergent coronary artery bypass graft (CABG), or Q-wave myocardial infarction. Acute procedural success was reported in 98.2% of patients who underwent PCIs with argatroban anticoagulation compared with 94.3% of historical control patients anticoagulated with heparin (p = NS). Among the 112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had non-Q-wave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt closure, and 1 had an impending closure (some patients may have experienced more than 1 event). No patients died.
# How Supplied
Argatroban Injection is supplied as a single-use vial, containing 250 mg/2.5 mL (100 mg/mL).
NDC 0143-9674-01 (Package of 1)
## Storage
Store the vials in original carton at 20° - 25° C (68° - 77° F). Do not freeze. Retain in the original carton to protect from light. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients of the risks associated with argatroban injection as well as the plan for regular monitoring during administration of the drug. Specifically, inform patients to report:
- The use of any other products known to affect bleeding.
- Any medical history that may increase the risk for bleeding, including a history of severe hypertension; recent lumbar puncture or spinal anesthesia; major surgery, especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations.
- Any bleeding signs or symptoms.
- The occurrence of any signs or symptoms of allergic reactions (e.g., airway reactions, skin reactions and vasodilation reactions).
# Precautions with Alcohol
Alcohol-Argatroban interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Argatroban
# Look-Alike Drug Names
- Argatroban - Aggrastat
- Argatroban - Orgaran
# Drug Shortage Status
# Price | Argatroban
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]
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# Overview
Argatroban is a direct thrombin inhibitor that is FDA approved for the {{{indicationType}}} of thrombosis in heparin-induced thrombocytopenia and prophylaxis in PCI. Common adverse reactions include dyspnea, hypotension, fever, diarrhea, chest pain, back pain, nausea, vomiting, headache, sepsis, and cardiac arrest.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Before administering argatroban, discontinue heparin therapy and obtain a baseline aPTT.
- Dosing Information
- Initial dose: 2 mcg/kg/min (continuous infusion)
- After the initiation of argatroban injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range
- Initial dose: 25 mcg/kg/min , administer a bolus of 350 mcg/kg via a large bore IV line over 3 to 5 minutes.
- Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed.
- The PCI procedure may proceed if the ACT is greater than 300 seconds.
- If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later
- If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later.
- Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Argatroban in adult patients.
### Non–Guideline-Supported Use
### Cardiovascular surgical procedure
- Dosing Information
- Continuous infusion of 0.3 to 0.96 mcg/kg/min
- There are limited studies that suggest its usefulness.[1]
### Cerebral thrombosis
- Dosing Information[2]
- Initial dose: 60 mg/day as a continuous IV infusion for 2 days
- Maintenance dose: 10 mg twice daily for 5 days
### Disseminated intravascular coagulation
- Dosing Information
- 0.7 mcg/kg/min[3]
### Extracorporeal circulation procedure
- Dosing Information
- 2 mcg/kg/min[4]
### Prophylaxis in Hemodialysis for Venous Catheter Occlusion
- As an alternative to heparin.
### Myocardial Infarction
- Dosing Information[5]
- Initial dose: 100 mcg/kg IV bolus
- Maintenance dose: 3 mcg/kg IV infusion
### Unstable Angina
- Dosing Information
- 0.5 to 5 mcg/kg/min over 4 hours[6]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Initial dose: 0.75 mcg/kg/min
- Check the aPTT two hours after the initiation of the argatroban infusion and adjust the dose to achieve the target aPTT.
- Increments of 0.1 to 0.25 mcg/kg/min for pediatric patients with normal hepatic function may be considered.
- Increments of 0.05 mcg/kg/min or lower for pediatric patients with impaired hepatic function may be considered.
- Initiate the infusion at a dose of 0.2 mcg/kg/min among seriously ill pediatric patients with impaired hepatic function
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Argatroban in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Argatroban in pediatric patients.
# Contraindications
- Patients with major bleeding.
- Patients with a history of hypersensitivity to argatroban. (Airway, skin, and generalized hypersensitivity reactions have been reported)
# Warnings
### Risk of Hemorrhage
- Hemorrhage can occur at any site in the body in patients receiving argatroban.
- Unexplained fall in hematocrit or blood pressure may indicate hemorrhage.
- Intracranial and retroperitoneal hemorrahage have been reported.
- The risk of hemorrahage with argatroban may be increased in severe hypertension; immediately following lumbar puncture, spinal anesthesia, major surgery (especially involving the brain, spinal cord, or eye), hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders, and gastrointestinal lesions such as ulcerations.
- Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding.
### Use in Hepatic Impairment
- When administering argatroban to patients with hepatic impairment, start with a lower dose and carefully titrate until the desired level of anticoagulation is achieved.
- Achievement of steady state aPTT levels may take longer and require more argatroban dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.
- Also, upon cessation of argatroban infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of argatroban.
- Avoid the use of high doses of argatroban in patients undergoing PCI who have clinically significant hepatic disease or AST/ALT levels ≥3 times the upper limit of normal.
### Laboratory Tests
- Anticoagulation effects associated with argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT).
- Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by argatroban, the therapeutic ranges for these tests have not been identified for argatroban therapy.
- In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring argatroban anticoagulant activity during the procedure.
- The concomitant use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
### Adverse Events in Patients with HIT (With or Without Thrombosis)
The following safety information is based on all 568 patients treated with argatroban in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events.
Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥2 g/dL, that led to a transfusion of ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding.
Table 4 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis).
Table 5 gives an overview of the most frequently observed non-hemorrhagic events sorted by decreasing frequency of occurrence (=2%) among argatroban-treated HIT/HITTS patients.
### Adverse Events in Patients with or at Risk for HIT Patients Undergoing PCI
The following safety information is based on 91 patients initially treated with argatroban and 21 patients subsequently re-exposed to argatroban for a total of 112 PCIs with argatroban anticoagulation. Adverse events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) events.
Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease ≥5 g/dL, that led to transfusion of ≥2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint.
The rate of major bleeding events in patients treated with argatroban in the PCI trials was 1.8%.
Table 7 gives an overview of the most frequently observed non-hemorrhagic events (>2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients.
There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatroban-treated-patients with or at risk for HIT undergoing PCI.
### Intracranial Bleeding In Other Populations
Increased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses. In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis.
The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively.
### Allergic Reactions
One hundred fifty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media.
Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order or frequency):
- Airway reactions (coughing, dyspnea): 10% or more
- Skin reactions (rash, bullous eruption): 1 to <10%
- General reactions (vasodilation): 1 to 10%
Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients.
## Postmarketing Experience
There is limited information regarding Argatroban Postmarketing Experience in the drug label.
# Drug Interactions
### Heparin
- If argatroban is to be initiated after cessation of heparin therapy, allow sufficient time for heparin’s effect on the aPTT to decrease prior to initiation of argatroban therapy.
### Oral Anticoagulant Agents
- Pharmacokinetic drug-drug interactions between argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated.
- However, the concomitant use of argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR).
### Aspirin/ Acetaminophen
- No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen.
### Thrombolytic Agents
- The safety and effectiveness of argatroban with thrombolytic agents have not been established.
### Glycoprotein IIb/IIIa Antagonists
- The safety and effectiveness of argatroban with glycoprotein IIb/IIIa antagonists have not been established.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
There are no adequate and well-controlled studies of argatroban use in pregnant women. Developmental studies performed in rats with argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Argatroban in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Argatroban during labor and delivery.
### Nursing Mothers
It is not known whether argatroban is excreted in human milk. Argatroban is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from argatroban, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
The safety and effectiveness of argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. Argatroban was studied among 18 seriously ill pediatric patients who required an alternative to heparin anticoagulation. Most patients were diagnosed with HIT or suspected HIT. Age ranges of patients were <6 months, n = 8; six months to <8 years, n = 6; 8 to 16 years, n = 4. All patients had serious underlying conditions and were receiving multiple concomitant medications. Thirteen patients received argatroban solely as a continuous infusion (no bolus dose). Dosing was initiated in the majority of these 13 patients at 1 mcg/kg/min. Dosing was titrated as needed to achieve and maintain an aPTT of 1.5 to 3 times the baseline value. Most patients required multiple dose adjustments to maintain anticoagulation parameters within the desired range. During the 30-day study period, thrombotic events occurred during argatroban administration to two patients and following argatroban discontinuation in three other patients. Major bleeding occurred among two patients; one patient experienced an intracranial hemorrhage after 4 days of argatroban therapy in the setting of sepsis and thrombocytopenia. Another patient completed 14 days of argatroban treatment in the study, but experienced an intracranial hemorrhage while receiving argatroban following completion of the study treatment period.
### Geriatic Use
Of the total number of subjects (1340) in clinical studies of argatroban, 35% were 65 and over. In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients had increased underlying conditions, which may predispose them to events. The studies were not sized appropriately to detect differences in safety between age groups.
### Gender
There are no clinically significant effects of gender on the pharmacokinetics or pharmacodynamics (e.g., aPTT) of argatroban in adults.
### Race
There is no FDA guidance on the use of Argatroban with respect to specific racial populations.
### Renal Impairment
No dosage adjustment is necessary in patients with renal dysfunction. The effect of renal disease on the pharmacokinetics of argatroban was studied in 6 subjects with normal renal function (mean Clcr = 95 ± 16 mL/min) and in 18 subjects with mild (mean Clcr = 64 ± 10 mL/min), moderate (mean Clcr = 41 ± 5.8 mL/min), and severe (mean Clcr = 5 ± 7 mL/min) renal impairment. The pharmacokinetics and pharmacodynamics of argatroban at dosages up to 5 mcg/kg/min were not significantly affected by renal dysfunction.
Use of argatroban was evaluated in a study of 12 patients with stable end-stage renal disease undergoing chronic intermittent hemodialysis. Argatroban was administered at a rate of 2 to 3 mcg/kg/min (begun at least 4 hours prior to dialysis) or as a bolus dose of 250 mcg/kg at the start of dialysis followed by a continuous infusion of 2 mcg/kg/min. Although these regimens did not achieve the goal of maintaining ACT values at 1.8 times the baseline value throughout most of the hemodialysis period, the hemodialysis sessions were successfully completed with both of these regimens. The mean ACTs produced in this study ranged from 1.39 to 1.82 times baseline, and the mean aPTTs ranged from 1.96 to 3.4 times the baseline. When argatroban was administered as a continuous infusion of 2 mcg/kg/min prior to and during a 4-hour hemodialysis session, approximately 20% was cleared through dialysis.
### Hepatic Impairment
Dose reduction and careful titration are required when administering argatroban to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population. Patients with hepatic impairment were not studied in percutaneous coronary intervention (PCI) trials. At a dose of 2.5 mcg/kg/min, hepatic impairment is associated with decreased clearance and increased elimination half-life of argatroban (to 1.9 mL/kg/min and 181 minutes, respectively, for patients with a Child-Pugh score greater than 6).
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Argatroban in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Argatroban in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Argatroban should not be mixed with other drugs prior to dilution.
Argatroban should be diluted in 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection to a final concentration of 1 mg/mL. The contents of each 2.5-mL vial should be diluted 100-fold by mixing with 250 mL of diluent. Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent.
The constituted solution must be mixed by repeated inversion of the diluent bag for 1 minute. Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing. Use of diluent at room temperature is recommended. The final solution must be clear before use. The pH of the intravenous solution prepared as recommended is 3.2 to 7.5. Prepared solutions should not be exposed to direct sunlight. No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
### Conversion to Oral Anticoagulant Therapy
- When converting patients from argatroban to oral anticoagulant therapy, consider the potential for combined effects on INR with co-administration of argatroban and warfarin.
- A loading dose of warfarin should not be used. Initiate therapy using the expected daily dose of warfarin.
- To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that argatroban and warfarin therapy be overlapped.
- There are insufficient data available to recommend the duration of the overlap.
- Measure INR daily while argatroban Injection and warfarin are co-administered. In general, with doses of argatroban injection up to 2 mcg/kg/min, argatroban injection can be discontinued when the INR is >4 on combined therapy.
- After argatroban injection is discontinued, repeat the INR measurement in 4 to 6 hours.
- If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.
- For doses greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban is less predictable.
- In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of argatroban injection to a dose of 2 mcg/kg/min.
- Repeat the INR on argatroban injection and warfarin 4 to 6 hours after reduction of the argatroban Injection dose and follow the process outlined above for administering argatroban injection at doses up to 2 mcg/kg/min.
### Monitoring
For use in HIT, therapy with argatroban injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of argatroban injection.
Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.
For use in PCI, therapy with argatroban injection is monitored using ACT. Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure. Obtain additional ACTs every 20 to 30 minutes during prolonged procedure.
In general, therapy with argatroban is monitored using the aPTT. Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of argatroban in patients without hepatic impairment. Dose adjustment may be required to attain the target aPTT. Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.
# IV Compatibility
There is limited information regarding the compatibility of Argatroban and IV administrations.
# Overdosage
- Excessive anticoagulation, with or without bleeding, may be controlled by discontinuing argatroban or by decreasing the argatroban dose.
- In clinical studies, anticoagulation parameters generally returned from therapeutic levels to baseline within 2 to 4 hours after discontinuation of the drug.
- Reversal of anticoagulant effect may take longer in patients with hepatic impairment.
- No specific antidote to argatroban is available; if life-threatening bleeding occurs and excessive plasma levels of argatroban are suspected, discontinue argatroban immediately and measure aPTT and other coagulation parameters.
- When argatroban was administered as a continuous infusion (2 mcg/kg/min) prior to and during a 4-hour hemodialysis session, approximately 20% of argatroban was cleared through dialysis.
- Single intravenous doses of argatroban at 200, 124, 150, and 200 mg/kg were lethal to mice, rats, rabbits, and dogs, respectively.
- The symptoms of acute toxicity were loss of lighting reflex, tremors, clonic convulsions, paralysis of hind limbs, and coma.
# Pharmacology
## Mechanism of Action
Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.
Argatroban inhibits thrombin with an inhibition constant (Ki) of 0.04 μM. At therapeutic concentrations, argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein).
Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.
## Structure
Argatroban is a synthetic direct thrombin inhibitor and the chemical name is 1-[5-[(aminoiminomethyl)amino]-1-oxo-2-(1,2,3,4-tetrahydro-3-methyl-8- quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.
The molecular formula of Argatroban is C23H36N6O5S•H2O. Its molecular weight is 526.66 g/mol. The structural formula is shown below:
Argatroban is a white, odorless crystalline powder that is freely soluble in glacial acetic acid, slightly soluble in ethanol, and insoluble in acetone, ethyl acetate, and ether. Argatroban injection is a sterile clear, colorless to pale yellow, slightly viscous solution. Argatroban is available in 250-mg (in 2.5-mL) single-use amber vials, with white flip-top caps. Each mL of sterile, nonpyrogenic solution contains 100 mg Argatroban. Inert ingredients: 1300 mg Propylene glycol, 800 mg Dehydrated alcohol.
## Pharmacodynamics
When argatroban is administered by continuous infusion, anticoagulant effects and plasma concentrations of argatroban follow similar, predictable temporal response profiles, with low intersubject variability. Immediately upon initiation of argatroban infusion, anticoagulant effects are produced as plasma argatroban concentrations begin to rise. Steady-state levels of both drug and anticoagulant effect are typically attained within 1 to 3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state plasma argatroban concentrations increase proportionally with dose (for infusion doses up to 40 mcg/kg/min in healthy subjects) and are well correlated with steady-state anticoagulant effects. For infusion doses up to 40 mcg/kg/min, argatroban increases in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the prothrombin time (PT), the International Normalized Ratio (INR), and the thrombin time (TT) in healthy volunteers and cardiac patients. Representative steady-state plasma argatroban concentrations and anticoagulant effects are shown below for argatroban infusion doses up to 10 mcg/kg/min.
Effect on International Normalized Ratio (INR): Because argatroban is a direct thrombin inhibitor, co-administration of argatroban and warfarin produces a combined effect on the laboratory measurement of the INR. However, concurrent therapy, compared to warfarin monotherapy, exerts no additional effect on vitamin K–dependent factor Xa activity.
The relationship between INR on co-therapy and warfarin alone is dependent on both the dose of argatroban and the thromboplastin reagent used. This relationship is influenced by the International Sensitivity Index (ISI) of the thromboplastin. Data for 2 commonly utilized thromboplastins with ISI values of 0.88 (Innovin, Dade) and 1.78 (Thromboplastin C Plus, Dade) are presented in Figure 2 for an argatroban dose of 2 mcg/kg/min. Thromboplastins with higher ISI values than shown result in higher INRs on combined therapy of warfarin and argatroban. These data are based on results obtained in normal individuals.
The graph above demonstrates the relationship between INR for warfarin alone and INR for warfarin co-administered with argatroban at a dose of 2 mcg/kg/min. To calculate INR for warfarin alone (INRW), based on INR for co-therapy of warfarin and argatroban (INRWA), when the argatroban dose is 2 mcg/kg/min, use the equation next to the appropriate curve. Example: At a dose of 2 mcg/kg/min and an INR performed with Thromboplastin A, the equation 0.19 + 0.57 (INRWA) = INRW would allow a prediction of the INR on warfarin alone (INRW). Thus, using an INRWA value of 4.0 obtained on combined therapy: INRW = 0.19 + 0.57 (4) = 2.47 as the value for INR on warfarin alone. The error (confidence interval) associated with a prediction is ± 0.4 units. Similar linear relationships and prediction errors exist for argatroban at a dose of 1 mcg/kg/min. Thus, for argatroban doses of 1 or 2 mcg/kg/min, INRW can be predicted from INRWA. For argatroban doses greater than 2 mcg/kg/min, the error associated with predicting INRW from INRWA is ± 1. Thus, INRW cannot be reliably predicted from INRWA at doses greater than 2 mcg/kg/min.
## Pharmacokinetics
### Distribution
Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent steady-state volume of distribution of 174 mL/kg (12.18 L in a 70-kg adult). Argatroban is 54% bound to human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34%, respectively.
### Metabolism
The main route of argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of each of the 4 known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. The primary metabolite (M1) exerts 3- to 5-fold weaker anticoagulant effects than argatroban. Unchanged argatroban is the major component in plasma. The plasma concentrations of M1 range between 0% and 20% of that of the parent drug. The other metabolites (M2 to M4) are found only in very low quantities in the urine and have not been detected in plasma or feces. These data, together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not an important elimination pathway in vivo.
Total body clearance is approximately 5.1 mL/kg/min (0.31 L/kg/hr) for infusion doses up to 40 mcg/kg/min. The terminal elimination half-life of argatroban ranges between 39 and 51 minutes.
There is no interconversion of the 21–(R):21–(S) diastereoisomers. The plasma ratio of these diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at 65:35 (± 2%).
### Excretion
Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which 14C-argatroban (5 mcg/kg/min) was infused for 4 hours into healthy subjects, approximately 65% of the radioactivity was recovered in the feces within 6 days of the start of infusion with little or no radioactivity subsequently detected. Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start of infusion. Little or no additional urinary radioactivity was subsequently detected. Average percent recovery of unchanged drug, relative to total dose, was 16% in urine and at least 14% in feces.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies with argatroban have not been performed.
Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte, and WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests, or the mouse micronucleus test.
Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.
# Clinical Studies
### Heparin-Induced Thrombocytopenia
The safety and efficacy of argatroban were evaluated in a historically controlled efficacy and safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These studies were comparable with regard to study design, study objectives, dosing regimens as well as study outline, conduct, and monitoring. In these studies, 568 adult patients were treated with argatroban and 193 adult patients made up the historical control group. Patients had a clinical diagnosis of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with thrombosis (HITTS heparin-induced thrombocytopenia and thrombosis syndrome) and were males or non-pregnant females between the age of 18 and 80 years old. HIT/HITTS was defined by a fall in platelet count to less than 100,000/μL or a 50% decrease in platelets after the initiation of heparin therapy with no apparent explanation other than HIT. Patients with HITTS also had an arterial or venous thrombosis documented by appropriate imaging techniques or supported by clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism, or other clinical indications of vascular occlusion. Patients who had documented histories of positive heparin-dependent antibody tests without current thrombocytopenia or heparin challenge (e.g., patients with latent disease) were also included if they required anticoagulation.
These studies did not include patients with documented unexplained aPTT >200% of control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HIT, a lumbar puncture within the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or a thrombotic stroke within the past 6 months unrelated to HIT.
The initial dose of argatroban was 2 mcg/kg/min. Two hours after the start of the argatroban infusion, an aPTT level was obtained and dose adjustments were made (up to a maximum of 10 mcg/kg/min) to achieve a steady-state aPTT value that was 1.5 to 3.0 times the baseline value, not to exceed 100 seconds. Overall the mean aPTT level for HIT and HITTS patients during the argatroban infusion increased from baseline values of 34 and 38 seconds, respectively, to 62.5 and 64.5 seconds, respectively.
The primary efficacy analysis was based on a comparison of event rates for a composite endpoint that included death (all causes), amputation (all causes) or new thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary analyses included evaluation of the event rates for the components of the composite endpoint as well as time-to-event analyses.
In Study 1, a total of 304 patients were enrolled as follows: active HIT (n = 129), active HITTS (n =144), or latent disease (n = 31). Among the 193 historical controls, 139 (72%) had active HIT, 46 (24%) had active HITTS, and 8 (4%) had latent disease. Within each group, those with active HIT and those with latent disease were analyzed together. Positive laboratory confirmation of HIT/HITTS by the heparin-induced platelet aggregation test or serotonin release assay was demonstrated in 174 of 304 (57%) argatroban-treated patients (i.e., in 80 with HIT or latent disease and 94 with HITTS) and in 149 of 193 (77%) historical controls (i.e., in 119 with HIT or latent disease and 30 with HITTS). The test results for the remainder of the patients and controls were either negative or not determined.
There was a significant improvement in the composite outcome in patients with HIT and HITTS treated with argatroban versus those in the historical control group (see Table 9). The components of the composite endpoint are shown in Table 9.
Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of argatroban by these analyses.
A time-to-event analysis for the composite endpoint is shown in Figure 3 for patients with HIT and Figure 4 for patients with HITTS.
In Study 2, a total of 264 patients were enrolled as follows: HIT (n = 125) or HITTS (n = 139). There was a significant improvement in the composite efficacy outcome for argatroban-treated patients, versus the same historical control group from Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS (41.0% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43.0%). Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of argatroban.
In Study 1, the mean (± SE) dose of argatroban administered was 2.0 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and 81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater than the baseline aPTT at the first assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS) following initiation of argatroban therapy.
No enhancement of aPTT response was observed in subjects receiving repeated administration of argatroban.
In Study 1, 53% of patients with HIT and 58% of patients with HITTS, had a recovery of platelet count by Day 3. Platelet Count Recovery was defined as an increase in platelet count to >100,000/μL or to at least 1.5-fold greater than the baseline count (platelet count at study initiation) by Day 3 of the study.
### Percutaneous Coronary Intervention (PCI) Patients with or at Risk for HIT
In 3 similarly designed trials, argatroban was administered to 91 patients with current or previous clinical diagnosis of HIT or heparin-dependent antibodies, who underwent a total of 112 percutaneous coronary interventions (PCIs) including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, or atherectomy. Among the 91 patients undergoing their first PCI with argatroban, notable ongoing or recent medical history included myocardial infarction (n = 35), unstable angina (n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The average age was 67.6 years (median 70.7, range 44 to 86), and the average weight was 82.5 kg (median 81.0 kg, range 49 to 141).
Twenty-one of the 91 patients had a repeat PCI using argatroban an average of 150 days after their initial PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were assessed against historical control populations who had been anticoagulated with heparin.
All patients received oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After venous or arterial sheaths were in place, anticoagulation was initiated with a bolus of argatroban of 350 mcg/kg via a large-bore intravenous line or through the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion of 25 mcg/kg/min was initiated to achieve a therapeutic activated clotting time (ACT) of 300 to 450 seconds. If necessary to achieve this therapeutic range, the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose of 150 mcg/kg could be given. Each patient’s ACT was checked 5 to 10 minutes following the bolus dose. The ACT was checked as clinically indicated. Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation of argatroban and when the ACT was less than 160 seconds.
If a patient required anticoagulation after the procedure, argatroban could be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours after this dose reduction and the dose of argatroban then was adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5 and 3 times baseline value (not to exceed 100 seconds).
In 92 of the 112 interventions (82%), the patient received the initial bolus of 350 mcg/kg and an initial infusion dose of 25 mcg/kg/min. The majority of patients did not require additional bolus dosing during the PCI procedure. The mean value for the initial ACT measurement after the start of dosing for all interventions was 379 sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value per intervention over all measurements taken during the procedure was 416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About 65% of patients had ACTs within the recommended range of 300 to 450 seconds throughout the procedure. The investigators did not achieve anticoagulation within the recommended range in about 23% of patients. However, in this small sample, patients with ACTs below 300 seconds did not have more coronary thrombotic events, and patients with ACTs over 450 seconds did not have higher bleeding rates.
Acute procedural success was defined as lack of death, emergent coronary artery bypass graft (CABG), or Q-wave myocardial infarction. Acute procedural success was reported in 98.2% of patients who underwent PCIs with argatroban anticoagulation compared with 94.3% of historical control patients anticoagulated with heparin (p = NS). Among the 112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had non-Q-wave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt closure, and 1 had an impending closure (some patients may have experienced more than 1 event). No patients died.
# How Supplied
Argatroban Injection is supplied as a single-use vial, containing 250 mg/2.5 mL (100 mg/mL).
NDC 0143-9674-01 (Package of 1)
## Storage
Store the vials in original carton at 20° - 25° C (68° - 77° F). Do not freeze. Retain in the original carton to protect from light. If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Inform patients of the risks associated with argatroban injection as well as the plan for regular monitoring during administration of the drug. Specifically, inform patients to report:
- The use of any other products known to affect bleeding.
- Any medical history that may increase the risk for bleeding, including a history of severe hypertension; recent lumbar puncture or spinal anesthesia; major surgery, especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations.
- Any bleeding signs or symptoms.
- The occurrence of any signs or symptoms of allergic reactions (e.g., airway reactions, skin reactions and vasodilation reactions).
# Precautions with Alcohol
Alcohol-Argatroban interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Argatroban
# Look-Alike Drug Names
- Argatroban - Aggrastat
- Argatroban - Orgaran
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Acova | |
5fdde094e75d8b0797f06faeab1d57f1f251582d | wikidoc | Angioedema | Angioedema
For reading more on patient information, click here
# Overview
Angioedema can be classified into the following types: Allergic angioedema, bradykinin mediated angioedema, drug induced angioedema, hereditary angioedema, and acquired angioedema. Angioedema should be differentiated from: Acute urticaria, anaphylaxis, food Allergy, and drug allergy. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. Possible complications include: Anaphylactic reaction and life-threatening airway blockage (if swelling occurs in the throat). Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12-36 hours and then subsides within 2-5 days. The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present. To prevent recurrent attacks of angioedema: Avoiding irritating the affected area, staying away from known allergens, and never taking medications that are not prescribed for the patient.
# Historical Perspective
- Dr Heinrich Quincke first described the clinical symptoms of angioedema in 1882.
- Sir William Osler explained in 1888 that some cases may have a hereditary etiology. He coined the term hereditary angio-neurotic edema.
# Classification
Angioedema can be classified into the following types:
- Allergic angioedema
- Bradykinin mediated angioedema
Drug induced angioedema
Hereditary angioedema
Type 1 - decreased levels of C1INH (85%);
Type 2 - normal levels but decreased function of C1INH (15%);
Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
- Drug induced angioedema
- Hereditary angioedema
Type 1 - decreased levels of C1INH (85%);
Type 2 - normal levels but decreased function of C1INH (15%);
Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
- Type 1 - decreased levels of C1INH (85%);
- Type 2 - normal levels but decreased function of C1INH (15%);
- Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
- Acquired angioedema
# Pathophysiology
Allergic reaction is a life-threatening cause of angioedema. Allergic reaction involves detection of a foreign substance by the immune system that results in histamine release into the bloodstream. The cause of angioedema cannot be identified in many cases. The following may cause angioedema:
- Hypersensitivity to: Animal dander (scales of shed skin), exposure to sunlight, cold or heat, foods such as berries, shellfish, fish, nuts, eggs, milk, and others
- Insect bites
- Estogen
- Drug allergies: Reaction to medications such as antibiotics (aztreonam, atovaquone and proguanil hydrochloride, penicillin, meropenem, and sulfa drugs), cexamethasone, ceftazidime, clobazam, cromolyn, cytomegalovirus immune globulin, niacin, nonsteroidal anti-inflammatory drugs (NSAIDs, blood pressure medicines (ACE inhibitors), pregabalin, prednisolone, rabeprazole, ritonavir, ustekinumab.
- Side Effect to Medications like: Aminohippurate, amobarbital sodium, boceprevir, caspofungin acetate, cefoxitin sodium, chloramphenicol sodium succinate, doxycycline, eslicarbazepine acetate, estramustine, hepatitis B immunoglobulin,hydroxyprogesterone caproate, imipenem-cilastatin,lacosamide, lincomycin hydrochloride, lisinopril and hydrochlorothiazide, meropenem, naratriptan, oxaprozin, oxytetracycline, polidocanol, potassium iodide, phenobarbital, quazepam, sodium aurothiomalate, sorafenib, streptomycin, sulfasalazine, trovafloxacin mesylate, zopiclone, sirolimus, cefadroxil, cefaclor, taliglucerase alfa, trichophyton mentagrophytes and trichophyton rubrum, trospium
- Pollen
- Infections or autoimmune diseases
Hives and angioedema may also occur after infections or with other illnesses (including autoimmune disorders such as lupus, leukemia and lymphoma). A form of angioedema runs in families and has different triggers, complications, and treatments. This is called hereditary angioedema.
- The progression to angioedema usually involves the pathway leading to activation of bradykinin.
- Bradykinin is a molecular peptide that causes vasodilation. Bradykinin mediated vasodilation results in rapid fluid accumulation in the interstitial space resulting in edema of the underlying tissue. Bradykinin is a known pain mediator and in addition to pain can be released in response to various different stimuli.
- Angioedema can also be mediated by mechanisms that interfere with bradykinin production or metabolism. ACE is one of the enzymes that degrades bradykinin and is blocked by ACE inhibitors, can result in angioedema as a medication side effect.
- A hereditary deficiency of C1-esterase inhibitor (C1INH) results in continuous activation of complement system resulting in excess production of bradykinin and kallikrein. C1-esterase inhibitor (C1INH) inhibits the conversion of C1 to C1r and C1s, which in turn activates other proteins of the complement system.
- Angioedema can also be due to an autoimmune disorder that results in antibody formation against C1INH. This is a type of acquired angioedema and is associated with the development of lymphoma.
- An episode of angioedema can be triggered in susceptible individuals as a result of consumption of foods that are vasodilators like alcohol and cinnamon. Medication like ibuprofen, acetaminophen and aspirin can increase the probability of an episode in some patients.
# Differentiating from other Diseases
- The following table outlines the differential diagnosis of various types of angioedema:
Angioedema should be differentiated from:
- Acute urticaria
- Anaphylaxis
- Food Allergy
- Drug allergy
# Risk Factors
- Common risk factors in the development of angioedema are previous history of allergic reactions, family history of allergic reactions, and other autoimmune disorders (atopia, eczema, etc).
# Natural History, Complications and Prognosis
- The stomach attacks in angioedema can last anywhere from 1-5 days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides.
- Possible complications include:
Anaphylactic reaction.
Life-threatening airway blockage (if swelling occurs in the throat).
- Anaphylactic reaction.
- Life-threatening airway blockage (if swelling occurs in the throat).
- Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days.
- Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12-36 hours and then subsides within 2-5 days.
# Diagnosis
## Symptoms
- History of recent exposure to an allergen (e.g. peanuts) should be inquired.
- Common Symptoms:
Swelling of face - the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands.
Difficulty breathing
Pain - the pain associated with the swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity.
Itching - the swelling can be itchy
Abdominal pain
Vomiting
Weakness
Abdominal cramping.
Swollen lining of the eyes (chemosis).
- Swelling of face - the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands.
- Difficulty breathing
- Pain - the pain associated with the swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity.
- Itching - the swelling can be itchy
- Abdominal pain
- Vomiting
- Weakness
- Abdominal cramping.
- Swollen lining of the eyes (chemosis).
- In Hereditary angioedema (HAE) there is usually no associated itch or urticaria, as it's not an allergic response. Patients with HAE can also have recurrent- episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, non-itchy splotchy/swirly rash.
## Physical Examination
- The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present.
- Swollen neck may be present.
- Stridor and wheeze may be heard in lung fields.
- Swollen genitals may be seen.
- Swollen extremities may be present.
- Slightly decreased sensations may be present in the affected areas due to compression of the nerves.
## Laboratory Findings
- The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, renal function, liver enzymes) are typically performed. Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; complement levels, especially depletion of complement factors 2 and 4, may indicate deficiency of C1-inhibitor.
- The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.
## Imaging Findings
- There are no specific imaging findings associated with angioedema, although in case of severe allergic reaction may show pleural effusion.
# Treatment
## Allergic Angioedema
In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine, marketed as Zyrtec, is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require steroid therapy, which generally leads to a good response.
## Bradykinin Mediated Angioedema
### Drug Induced Angioedema
In ACE inhibitor use, the medication needs to be discontinued, and all similar drugs need to be avoided. There is a certain degree of controversy whether angiotensin II receptor antagonists are safe in patients with a previous attack of angioedema.
### Hereditary Angioedema
In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.
The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1-INH concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. Fresh Frozen Plasma (FFP) can be used as an alternative to C1-INH concentrate.
In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Intubation is required in these situations to prevent respiratory arrest and risk of death.
Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. This often involves male sex hormones (androgens), which increase production of C1-INH in the liver through an as yet unknown mechanism. The dose should be kept as low as possible because of its frequent adverse effects. The use of androgens is particularly problematic in children and they must not be taken during pregnancy. Several cases in which patients developed benign liver tumours during treatment with the androgen danazol resulted in the substance being taken off the market in Germany at the beginning of 2005.
As an alternative, drugs known as fibrinolysis inhibitors, such as tranexamic acid, are used, although their effect is comparatively weak and their potential for side effects is questionable.
Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1-1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5-7 days.
## Acquired Angioedema
In acquired angioedema types I and II and non-histaminergic angioedema, antifibrinolytics such as tranexamic acid or ε-aminocaproic acid may be effective. Cinnarizine may also be useful because it blocks the activation of C4 and can be used in patients with liver disease while androgens cannot.
## Prevention
To prevent recurrent attacks of angioedema:
- Avoiding irritating the affected area.
- Staying away from known allergens.
- Never taking medications that are not prescribed for the patient.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas.
- Angioedema. Adapted from Dermatology Atlas. | Angioedema
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
For reading more on patient information, click here
# Overview
Angioedema can be classified into the following types: Allergic angioedema, bradykinin mediated angioedema, drug induced angioedema, hereditary angioedema, and acquired angioedema. Angioedema should be differentiated from: Acute urticaria, anaphylaxis, food Allergy, and drug allergy. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides. Possible complications include: Anaphylactic reaction and life-threatening airway blockage (if swelling occurs in the throat). Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days. Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12-36 hours and then subsides within 2-5 days. The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present. To prevent recurrent attacks of angioedema: Avoiding irritating the affected area, staying away from known allergens, and never taking medications that are not prescribed for the patient.
# Historical Perspective
- Dr Heinrich Quincke first described the clinical symptoms of angioedema in 1882. [1]
- Sir William Osler explained in 1888 that some cases may have a hereditary etiology. He coined the term hereditary angio-neurotic edema.[2]
# Classification
Angioedema can be classified into the following types:[3] [4]
- Allergic angioedema
- Bradykinin mediated angioedema
Drug induced angioedema
Hereditary angioedema
Type 1 - decreased levels of C1INH (85%);
Type 2 - normal levels but decreased function of C1INH (15%);
Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
- Drug induced angioedema
- Hereditary angioedema
Type 1 - decreased levels of C1INH (85%);
Type 2 - normal levels but decreased function of C1INH (15%);
Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
- Type 1 - decreased levels of C1INH (85%);
- Type 2 - normal levels but decreased function of C1INH (15%);
- Type 3 - no detectable abnormality in C1INH, occurs in an X-linked dominant fashion and therefore mainly affects women; it can be exacerbated by pregnancy and use of hormonal contraception (originally described by Bork et al in 2000, exact frequency uncertain).It has been linked with mutations in the factor XII gene.
- Acquired angioedema
# Pathophysiology
Allergic reaction is a life-threatening cause of angioedema. Allergic reaction involves detection of a foreign substance by the immune system that results in histamine release into the bloodstream. The cause of angioedema cannot be identified in many cases. The following may cause angioedema:
- Hypersensitivity to: Animal dander (scales of shed skin), exposure to sunlight, cold or heat, foods such as berries, shellfish, fish, nuts, eggs, milk, and others
- Insect bites
- Estogen[5]
- Drug allergies: Reaction to medications such as antibiotics (aztreonam, atovaquone and proguanil hydrochloride, penicillin, meropenem, and sulfa drugs), cexamethasone, ceftazidime, clobazam, cromolyn, cytomegalovirus immune globulin, niacin, nonsteroidal anti-inflammatory drugs (NSAIDs, blood pressure medicines (ACE inhibitors), pregabalin, prednisolone, rabeprazole, ritonavir, ustekinumab.
- Side Effect to Medications like: Aminohippurate, amobarbital sodium, boceprevir, caspofungin acetate, cefoxitin sodium, chloramphenicol sodium succinate, doxycycline, eslicarbazepine acetate, estramustine, hepatitis B immunoglobulin,hydroxyprogesterone caproate, imipenem-cilastatin,lacosamide, lincomycin hydrochloride, lisinopril and hydrochlorothiazide, meropenem, naratriptan, oxaprozin, oxytetracycline, polidocanol, potassium iodide, phenobarbital, quazepam, sodium aurothiomalate, sorafenib, streptomycin, sulfasalazine, trovafloxacin mesylate, zopiclone, sirolimus, cefadroxil, cefaclor, taliglucerase alfa, trichophyton mentagrophytes and trichophyton rubrum, trospium
- Pollen
- Infections or autoimmune diseases
Hives and angioedema may also occur after infections or with other illnesses (including autoimmune disorders such as lupus, leukemia and lymphoma). A form of angioedema runs in families and has different triggers, complications, and treatments. This is called hereditary angioedema.
- The progression to angioedema usually involves the pathway leading to activation of bradykinin.[6][7]
- Bradykinin is a molecular peptide that causes vasodilation. Bradykinin mediated vasodilation results in rapid fluid accumulation in the interstitial space resulting in edema of the underlying tissue. Bradykinin is a known pain mediator and in addition to pain can be released in response to various different stimuli.
- Angioedema can also be mediated by mechanisms that interfere with bradykinin production or metabolism. ACE is one of the enzymes that degrades bradykinin and is blocked by ACE inhibitors, can result in angioedema as a medication side effect.
- A hereditary deficiency of C1-esterase inhibitor (C1INH) results in continuous activation of complement system resulting in excess production of bradykinin and kallikrein. C1-esterase inhibitor (C1INH) inhibits the conversion of C1 to C1r and C1s, which in turn activates other proteins of the complement system.
- Angioedema can also be due to an autoimmune disorder that results in antibody formation against C1INH. This is a type of acquired angioedema and is associated with the development of lymphoma.
- An episode of angioedema can be triggered in susceptible individuals as a result of consumption of foods that are vasodilators like alcohol and cinnamon. Medication like ibuprofen, acetaminophen and aspirin can increase the probability of an episode in some patients.
# Differentiating [disease name] from other Diseases
- The following table outlines the differential diagnosis of various types of angioedema:
Angioedema should be differentiated from:
- Acute urticaria
- Anaphylaxis
- Food Allergy
- Drug allergy
# Risk Factors
- Common risk factors in the development of angioedema are previous history of allergic reactions, family history of allergic reactions, and other autoimmune disorders (atopia, eczema, etc).
# Natural History, Complications and Prognosis
- The stomach attacks in angioedema can last anywhere from 1-5 days on average, and can require hospitalization for aggressive pain management and hydration. Abdominal attacks have also been known to cause a significant increase in the patient's white blood cell count, usually in the vicinity of 13-30,000. As the symptoms begin to diminish, the white count slowly begins to decrease, returning to normal when the attack subsides.
- Possible complications include:
Anaphylactic reaction.
Life-threatening airway blockage (if swelling occurs in the throat).
- Anaphylactic reaction.
- Life-threatening airway blockage (if swelling occurs in the throat).
- Angioedema that does not affect the breathing may be uncomfortable, but is usually harmless and goes away in a few days.
- Predicting where and when the next episode of edema will occur is impossible. Most patients have an average of one episode per month, but there are also patients who have weekly episodes or only one or two episodes per year. The triggers can vary and include infections, minor injuries, mechanical irritation, operations or stress. In most cases, edema develops over a period of 12-36 hours and then subsides within 2-5 days.
# Diagnosis
## Symptoms
- History of recent exposure to an allergen (e.g. peanuts) should be inquired.
- Common Symptoms:
Swelling of face - the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands.
Difficulty breathing
Pain - the pain associated with the swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity.
Itching - the swelling can be itchy
Abdominal pain
Vomiting
Weakness
Abdominal cramping.
Swollen lining of the eyes (chemosis).
- Swelling of face - the skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue, swell up over the period of minutes to several hours. The swelling can also occur elsewhere, typically in the hands.
- Difficulty breathing
- Pain - the pain associated with the swellings varies from mildly uncomfortable to agonizing pain, depending on its location and severity.
- Itching - the swelling can be itchy
- Abdominal pain
- Vomiting
- Weakness
- Abdominal cramping.
- Swollen lining of the eyes (chemosis).
- In Hereditary angioedema (HAE) there is usually no associated itch or urticaria, as it's not an allergic response. Patients with HAE can also have recurrent* episodes (often called "attacks") of abdominal pain, usually accompanied by intense vomiting, weakness, and in some cases, watery diarrhea, and an unraised, non-itchy splotchy/swirly rash.
## Physical Examination
- The skin of the face, normally around the mouth, and the mucosa of the mouth and/or throat, as well as the tongue are swollen up. Urticaria (hives) may develop simultaneously. Rash may be present.
- Swollen neck may be present.
- Stridor and wheeze may be heard in lung fields.
- Swollen genitals may be seen.
- Swollen extremities may be present.
- Slightly decreased sensations may be present in the affected areas due to compression of the nerves.
## Laboratory Findings
- The diagnosis is made on the clinical picture. Routine blood tests (complete blood count, electrolytes, renal function, liver enzymes) are typically performed. Mast cell tryptase levels may be elevated if the attack was due to an acute allergic (anaphylactic) reaction. When the patient has been stabilized, particular investigations may clarify the exact cause; complement levels, especially depletion of complement factors 2 and 4, may indicate deficiency of C1-inhibitor.
- The hereditary form (HAE) often goes undetected for a long time, as its symptoms resemble those of more common disorders, such as allergy or intestinal colic. An important clue is the failure of angioedema to respond to antihistamines or steroids, a characteristic that distinguishes it from allergic reactions. It is particularly difficult to diagnose HAE in patients whose episodes are confined to the gastrointestinal tract. Besides a family history of the disease, only a laboratory analysis can provide final confirmation. In this analysis, it is usually a reduced complement factor C4, rather than the C1-INH deficiency itself, that is detected. The former is used during the reaction cascade in the complement system of immune defense, which is permanently overactive due to the lack of regulation by C1-INH.
## Imaging Findings
- There are no specific imaging findings associated with angioedema, although in case of severe allergic reaction may show pleural effusion.
# Treatment
## Allergic Angioedema
In allergic angioedema, avoidance of the allergen and use of antihistamines may prevent future attacks. Cetirizine, marketed as Zyrtec, is a commonly prescribed antihistamine for angioedema. Some patients have reported success with the combination of a nightly low dose of cetirizine to moderate the frequency and severity of attacks, followed by a much higher dose when an attack does appear. Severe angioedema cases may require desensitization to the putative allergen, as mortality can occur. Chronic cases require steroid therapy, which generally leads to a good response.
## Bradykinin Mediated Angioedema
### Drug Induced Angioedema
In ACE inhibitor use, the medication needs to be discontinued, and all similar drugs need to be avoided. There is a certain degree of controversy whether angiotensin II receptor antagonists are safe in patients with a previous attack of angioedema.
### Hereditary Angioedema
In hereditary angioedema, specific stimuli that have previously luxated attacks may need to be avoided in the future.
The aim of acute treatment is to halt progression of the edema as quickly as possible, which can be life-saving, particularly if the swelling is in the larynx. In Germany, most acute treatment consists of C1-INH concentrate from donor blood, which must be administered intravenously. In an emergency, fresh frozen blood plasma, which also contains C1-INH, can also be used. However, in most European countries, C1-INH concentrate is only available to patients who are participating in special programmes. Fresh Frozen Plasma (FFP) can be used as an alternative to C1-INH concentrate.
In severe cases, stridor of the airway occurs, with gasping or wheezy inspiratory breath sounds and decreasing oxygen levels. Intubation is required in these situations to prevent respiratory arrest and risk of death.
Patients in whom episodes occur at least once a month or who are at high risk of developing laryngeal edema require long-term prophylaxis. This often involves male sex hormones (androgens), which increase production of C1-INH in the liver through an as yet unknown mechanism. The dose should be kept as low as possible because of its frequent adverse effects. The use of androgens is particularly problematic in children and they must not be taken during pregnancy. Several cases in which patients developed benign liver tumours during treatment with the androgen danazol resulted in the substance being taken off the market in Germany at the beginning of 2005.
As an alternative, drugs known as fibrinolysis inhibitors, such as tranexamic acid, are used, although their effect is comparatively weak and their potential for side effects is questionable.
Short-term prophylaxis is normally administered before surgery or dental treatment. In Germany, C1-INH concentrate is used for this and given 1-1.5 hours before the procedure. In countries where C1-inhibitor concentrate is not available or only available in an emergency (laryngeal edema), high-dose androgen treatment is administered for 5-7 days.
## Acquired Angioedema
In acquired angioedema types I and II and non-histaminergic angioedema, antifibrinolytics such as tranexamic acid or ε-aminocaproic acid may be effective. Cinnarizine may also be useful because it blocks the activation of C4 and can be used in patients with liver disease while androgens cannot.
## Prevention
To prevent recurrent attacks of angioedema:
- Avoiding irritating the affected area.
- Staying away from known allergens.
- Never taking medications that are not prescribed for the patient.
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8]
- Angioedema. Adapted from Dermatology Atlas.[8] | https://www.wikidoc.org/index.php/Acquired_angioedema | |
4abe591c7e14a7990ac045de7e479b607502ba55 | wikidoc | Centromere | Centromere
# Overview
The centromere is a region, often found in the middle of the chromosome, involved in cell division and the control of gene expression.
# Function
The centromere is together with telomeres and origin of replications one of the essential parts of any eukaryotic chromosomes. The centromere is usually defined by specific DNA sequences which are in higher eukaryotes typical tandem repetitive sequences, often called "satellite DNA". These sequences bind specific proteins called "cen"-Proteins. During mitosis the centromeres can be identified in particular during the metaphase stage as a constriction at the chromosome. At this centromeric constriction the two mostly identical halves of the chromosome, the sister chromatids, are held together until late metaphase. During mitotic division, a transient structure called kinetochore is formed on top of the centromeres. The kinetochores are the sites where the spindle fibers attach. Kinetochores and the spindle apparatus are responsible for the movement of the two sister chromatids to opposite poles of dividing cell nucleus during anaphase. Usually the mitosis is immediately followed by a cell division cytokinesis. However, mitosis and cytokinesis are separate processes and can be uncoupled.
A centromere functions in sister chromatid adhesion, kinetochore formation, and pairing of homologous chromosomes.
A centromere is the region where sister chromatids join in the double chromosomal structure during mitosis, prophase and metaphase. The centromere is also where kinetochore formation takes place: proteins bind on the centromeres that form an anchor point for the spindle formation required for the pull of chromosomes toward the centrioles during the anaphase and telophase of mitosis.
When the centromere doesn't function properly, the chromosomes don't align and separate properly, resulting in the wrong number of chromosomes in the daughter cells (aneuploidy), and conditions such as Down syndrome, if the cells survive at all.
# Centromere Positions
Each chromosome has two arms, labeled p (the shorter of the two) and q (the longer). They can be connected in either metacentric, submetacentric, acrocentric or telocentric manner. (While the p arm is named for petite meaning small, the q arm is named thus simply because it follows p in the alphabet.)
## Metacentric
If both arms are equal in length, the chromosome is said to be metacentric.
Robertsonian -- fusion of 2 p arms by centric fusion to form metacentric chromosome.
## Submetacentric
If arms' lengths are unequal, the chromosome is said to be submetacentric
## Acrocentric
If the p (short) arm is so short that is hard to observe, but still present, then the chromosome is acrocentric (The "acro-" in acrocentric refers to the Greek word for "peak.").
There are five acrocentric chromosomes in the human genome: 13, 14, 15, 21 and 22. These five chromosomes are the site of genes encoding rRNAs.
## Telocentric
A telocentric chromosome's centromere is located at the terminal end of the chromosome. Telomeres may extend from both ends of the chromosome. All mouse chromosomes are telocentric ; humans do not possess any telocentric chromosomes.
# The centromeric sequence
In most eukaryotes, the centromere has no defined DNA sequence. It typically consists of large arrays of repetitive DNA (e.g. satellite DNA) where the sequence within individual repeat elements is similar but not identical. In humans, the primary centromeric repeat unit is called α-satellite (or alphoid), although a number of other sequence types are found in this region. However, in budding yeasts the centromere region is relatively small (about 125 bp DNA) and contains two highly conserved DNA sequences that serve as binding sites for essential kinetochore proteins.
# Inheritance
Epigenetic inheritance plays a major role in specifying the centromere in most organisms. The daughter chromosomes will assemble centromeres in the same place as the parent chromosome, independent of sequence. However, there must still be some original way in which the centromere is specified, even if it is subsequently propagated epigenetically.
# Structure
The centromeric DNA is normally in a heterochromatin state, which is essential for the recruitment of the cohesin complex that mediates sister chromatid cohesion after DNA replication as well as coordinating sister chromatid separation during anaphase. In this chromatin, the normal histone H3 is replaced with a centromere-specific variant, CENP-A in humans (Lodish et al. 2004). The presence of CENP-A is believed to be important for the assembly of the kinetochore on the centromere. CENP-C has been shown to localise almost exclusively to these regions of CENP-A associated chromatin.
In the yeast Schizosaccharomyces pombe (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to RNAi. In nematodes such as Caenorhabditis elegans, some plants, and the insect orders Lepidoptera and Hemiptera, chromosomes are "holocentric", indicating that there is not a primary site of microtubule attachments or a primary constriction, and a "diffuse" kinetochore assembles along the entire length of the chromosome.
# Centromeric aberrations
In rare cases in humans, neocentromeres can form at new sites on the chromosome. This must be coupled with the inactivation of the previous centromere since chromosomes with two functional centromeres (Dicentric chromosome) will result in chromosome breakage during mitosis.
In some unusual cases human neocentromeres have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether.
Centromere proteins are also the autoantigenic target for some anti-nuclear antibodies such as anti-centromere antibodies
# Related links
- Monopolin
- Genetics
- Cell biology
- Chromatid
- Diploid | Centromere
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The centromere is a region, often found in the middle of the chromosome, involved in cell division and the control of gene expression.
# Function
The centromere is together with telomeres and origin of replications one of the essential parts of any eukaryotic chromosomes. The centromere is usually defined by specific DNA sequences which are in higher eukaryotes typical tandem repetitive sequences, often called "satellite DNA". These sequences bind specific proteins called "cen"-Proteins. During mitosis the centromeres can be identified in particular during the metaphase stage as a constriction at the chromosome. At this centromeric constriction the two mostly identical halves of the chromosome, the sister chromatids, are held together until late metaphase. During mitotic division, a transient structure called kinetochore is formed on top of the centromeres. The kinetochores are the sites where the spindle fibers attach. Kinetochores and the spindle apparatus are responsible for the movement of the two sister chromatids to opposite poles of dividing cell nucleus during anaphase. Usually the mitosis is immediately followed by a cell division cytokinesis. However, mitosis and cytokinesis are separate processes and can be uncoupled.
A centromere functions in sister chromatid adhesion, kinetochore formation, and pairing of homologous chromosomes.
A centromere is the region where sister chromatids join in the double chromosomal structure during mitosis, prophase and metaphase. The centromere is also where kinetochore formation takes place: proteins bind on the centromeres that form an anchor point for the spindle formation required for the pull of chromosomes toward the centrioles during the anaphase and telophase of mitosis.
When the centromere doesn't function properly, the chromosomes don't align and separate properly, resulting in the wrong number of chromosomes in the daughter cells (aneuploidy), and conditions such as Down syndrome, if the cells survive at all.
[1]
# Centromere Positions
Each chromosome has two arms, labeled p (the shorter of the two) and q (the longer). They can be connected in either metacentric, submetacentric, acrocentric or telocentric manner. (While the p arm is named for petite meaning small, the q arm is named thus simply because it follows p in the alphabet.)
## Metacentric
If both arms are equal in length, the chromosome is said to be metacentric.
Robertsonian -- fusion of 2 p arms by centric fusion to form metacentric chromosome.
## Submetacentric
If arms' lengths are unequal, the chromosome is said to be submetacentric
## Acrocentric
If the p (short) arm is so short that is hard to observe, but still present, then the chromosome is acrocentric (The "acro-" in acrocentric refers to the Greek word for "peak.").
There are five acrocentric chromosomes in the human genome: 13, 14, 15, 21 and 22. These five chromosomes are the site of genes encoding rRNAs.
## Telocentric
A telocentric chromosome's centromere is located at the terminal end of the chromosome. Telomeres may extend from both ends of the chromosome. All mouse chromosomes are telocentric [2]; humans do not possess any telocentric chromosomes.
# The centromeric sequence
In most eukaryotes, the centromere has no defined DNA sequence. It typically consists of large arrays of repetitive DNA (e.g. satellite DNA) where the sequence within individual repeat elements is similar but not identical. In humans, the primary centromeric repeat unit is called α-satellite (or alphoid), although a number of other sequence types are found in this region. However, in budding yeasts the centromere region is relatively small (about 125 bp DNA) and contains two highly conserved DNA sequences that serve as binding sites for essential kinetochore proteins.
# Inheritance
Epigenetic inheritance plays a major role in specifying the centromere in most organisms. The daughter chromosomes will assemble centromeres in the same place as the parent chromosome, independent of sequence. However, there must still be some original way in which the centromere is specified, even if it is subsequently propagated epigenetically.
# Structure
The centromeric DNA is normally in a heterochromatin state, which is essential for the recruitment of the cohesin complex that mediates sister chromatid cohesion after DNA replication as well as coordinating sister chromatid separation during anaphase. In this chromatin, the normal histone H3 is replaced with a centromere-specific variant, CENP-A in humans (Lodish et al. 2004). The presence of CENP-A is believed to be important for the assembly of the kinetochore on the centromere. CENP-C has been shown to localise almost exclusively to these regions of CENP-A associated chromatin.
In the yeast Schizosaccharomyces pombe (and probably in other eukaryotes), the formation of centromeric heterochromatin is connected to RNAi.[3] In nematodes such as Caenorhabditis elegans, some plants, and the insect orders Lepidoptera and Hemiptera, chromosomes are "holocentric", indicating that there is not a primary site of microtubule attachments or a primary constriction, and a "diffuse" kinetochore assembles along the entire length of the chromosome.
# Centromeric aberrations
In rare cases in humans, neocentromeres can form at new sites on the chromosome. This must be coupled with the inactivation of the previous centromere since chromosomes with two functional centromeres (Dicentric chromosome) will result in chromosome breakage during mitosis.
In some unusual cases human neocentromeres have been observed to form spontaneously on fragmented chromosomes. Some of these new positions were originally euchromatic and lack alpha satellite DNA altogether.
Centromere proteins are also the autoantigenic target for some anti-nuclear antibodies such as anti-centromere antibodies
# Related links
- Monopolin
- Genetics
- Cell biology
- Chromatid
- Diploid | https://www.wikidoc.org/index.php/Acrocentric | |
f05c095a709aa03b11db1f04ec4d52d1576cf6f4 | wikidoc | Acrophobia | Acrophobia
# Overview
Acrophobia (from Greek Template:Polytonic, meaning "summit") is an extreme or irrational fear of heights. It belongs to a category of specific phobias, called space and motion discomfort that share both similar etiology and options for treatment.
Acrophobia can be dangerous, as sufferers can experience a panic attack in a high place and become too agitated to get themselves down safely. Some acrophobics also suffer from urges to throw themselves off high places, despite not being suicidal.
"Vertigo" is often used, incorrectly, to describe the fear of heights, but it is more accurately described as a spinning sensation, which may be caused by looking down from a high place, as well as by some other stimuli. Vertigo is qualified as height vertigo when referring to dizziness triggered by heights.
# Etiology
Traditionally, acrophobia has been attributed, like other irrational fears, to conditioning or a traumatic experience involving heights. Recent studies have cast doubt on this explanation; fear of falling, along with fear of loud noises, is one of the most commonly suggested inborn or non-associative fears. The newer non-association theory is that fear of heights is an evolved adaptation to a prehistory where falls posed a significant danger. The degree of fear varies and the term phobia is reserved for those at the extreme end of the spectrum. It has been argued by researchers that fear of heights is an instinct found in many mammals, including domestic animals and human beings. There have been experiments showing toddler babies and cats of various ages being terrified of venturing onto a glass floor with a view of a few meters of 'fall-space' below it. An extreme fear however can interfere with the challenges of everyday life, such as climbing up a flight of stairs or a ladder, or standing on a chair, table, (etc.).
A possible contributing factor is dysfunction in maintaining balance. In this case the anxiety is both well founded and secondary. The human balance system integrates proprioceptive, vestibular and nearby visual cues to reckon position and motion. As height increases visual cues recede and balance becomes poorer even in normal people. However most people respond by shifting to more reliance on the proprioceptive and vestibular branches of the equilibrium system.
An acrophobic, on the other hand, continues to overrely on visual signals whether because of inadequate vestibular function or incorrect strategy. Locomotion at a high elevation requires more than normal visual processing. The visual cortex becomes overloaded resulting in confusion. Some proponents of the alternative view of acrophobia warn that it may be ill-advised to encourage acrophobics to expose themselves to height without first resolving the vestibular issues. Research is underway at several clinics. | Acrophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Acrophobia (from Greek Template:Polytonic, meaning "summit") is an extreme or irrational fear of heights. It belongs to a category of specific phobias, called space and motion discomfort that share both similar etiology and options for treatment.
Acrophobia can be dangerous, as sufferers can experience a panic attack in a high place and become too agitated to get themselves down safely. Some acrophobics also suffer from urges to throw themselves off high places, despite not being suicidal.
"Vertigo" is often used, incorrectly, to describe the fear of heights, but it is more accurately described as a spinning sensation, which may be caused by looking down from a high place, as well as by some other stimuli. Vertigo is qualified as height vertigo when referring to dizziness triggered by heights.
# Etiology
Traditionally, acrophobia has been attributed, like other irrational fears, to conditioning or a traumatic experience involving heights. Recent studies have cast doubt on this explanation;[1] fear of falling, along with fear of loud noises, is one of the most commonly suggested inborn or non-associative fears. The newer non-association theory is that fear of heights is an evolved adaptation to a prehistory where falls posed a significant danger. The degree of fear varies and the term phobia is reserved for those at the extreme end of the spectrum. It has been argued by researchers that fear of heights is an instinct found in many mammals, including domestic animals and human beings. There have been experiments showing toddler babies and cats of various ages being terrified of venturing onto a glass floor with a view of a few meters of 'fall-space' below it. [2]An extreme fear however can interfere with the challenges of everyday life, such as climbing up a flight of stairs or a ladder, or standing on a chair, table, (etc.).
A possible contributing factor is dysfunction in maintaining balance. In this case the anxiety is both well founded and secondary. The human balance system integrates proprioceptive, vestibular and nearby visual cues to reckon position and motion.[3][4] As height increases visual cues recede and balance becomes poorer even in normal people. [5] However most people respond by shifting to more reliance on the proprioceptive and vestibular branches of the equilibrium system.
An acrophobic, on the other hand, continues to overrely on visual signals whether because of inadequate vestibular function or incorrect strategy. Locomotion at a high elevation requires more than normal visual processing. The visual cortex becomes overloaded resulting in confusion. Some proponents of the alternative view of acrophobia warn that it may be ill-advised to encourage acrophobics to expose themselves to height without first resolving the vestibular issues. Research is underway at several clinics.[6] | https://www.wikidoc.org/index.php/Acrophobia | |
06f6ce8d0fa22cce13387c122d78f42fe3fea42a | wikidoc | Acrylamide | Acrylamide
# Overview
The chemical compound acrylamide (acrylic amide) has the chemical formula C3H5NO. Its IUPAC name is 2-propenamide. It is a white odourless crystalline solid, soluble in water, ethanol, ether and chloroform. Acrylamide is incompatible with acids, bases, oxidizing agents, iron and iron salts. It decomposes non thermally to form ammonia and thermal decomposition produces carbon monoxide, carbon dioxide and oxides of nitrogen.
Most acrylamide is used to synthesize polyacrylamides which find many uses as water-soluble thickeners. These include use in wastewater treatment, gel electrophoresis (SDS-PAGE), papermaking, ore processing, and the manufacture of permanent press fabrics. Some acrylamide is used in the manufacture of dyes and the manufacture of other monomers.
Acrylamide was accidentally discovered in foods in April 2002 by scientists in Sweden when they found large amounts of the chemical in starchy foods, such as potato chips, French fries, and bread. It is not found in food which has been boiled.
# Occurrence in daily life
Acrylamide in fried or baked goods is produced by the reaction between asparagine and reducing sugars (fructose, glucose, etc.) or reactive carbonyls. Acrylamide in olives and prune juice comes through another process. It has been suggested that environmental pathways, such as the breakdown of the herbicide glyphosate (Roundup), are sources too. Smoking is also a major acrylamide producer. Estimates for the proportion in the diet coming from the consumption of coffee range from twenty to forty percent. Acrylamide cannot be created by boiling, and very few uncooked foods contain any detectable amounts. Browning during baking, frying or deep-frying will produce acrylamide and over-cooking of foods will produce large amounts of acrylamide. Acrylamides can also be created during microwaving.
# Reduction of acrylamide formation
## Storage
In the case of potatoes for instance the storage temperature should not drop below 8°C. When the temperature is as low as 4°C the fructose content rises sharply, so that the acrylamide formation during baking or deep-frying will be higher.
## Raw Material
New varieties of potatoes are being bred that produce less or no acrylamide.
## Production methods
In many cases it is advisable to lower the maximum temperature during baking. Also new production methods such as vacuum frying may lower the acrylamide formation.
When silicone is used as a foam inhibitor in deep-frying fats in the food industry the acrylamide content is doubled.
## Recipe Formulation
Asparaginase, a naturally-occurring enzyme, can be added to bread or potato mixtures to reduce formation of acrylamide during cooking
# Potential health risk
There is evidence that exposure to large doses can cause damage to the male reproductive glands. Direct exposure to pure acrylamide by inhalation, skin absorption, or eye contact irritates the exposed mucous membranes, e.g. the nose, and can also cause sweating, urinary incontinence, nausea, myalgia, speech disorders, numbness, paresthesia, and weakened legs and hands. In addition, the acrylamide monomer is a potent neurotoxin, causing the disassembly or rearrangement of intermediate filaments. Ingested acrylamide is metabolised to a chemically reactive epoxide, glycidamide.
## Cancer
According to a 2005 review, acrylamide reliably produces various types of cancer in experimental mice and rats. However, studies in human populations have failed to produce consistent results, and it remains unclear whether this is due to a reduced risk in a natural setting or the methodological difficulties inherent in such studies. For example, it might be difficult to isolate the effects of acrylamide because it is so ubiquitous in western diets.
## Public awareness
In 2002-04-24 the Swedish National Food Administration (Livsmedelsverket) announced that acrylamide can be found in baked and fried starchy foods, such as potato chips, breads and cookies. Concern was raised mainly because of the carcinogenic effects of acrylamide. This was followed by a strong but short-lived interest from the press. On 2005-08-26, California attorney general Bill Lockyer filed a lawsuit against top makers of french fries and potato chips to warn consumers of the potential risk from consuming acrylamide. | Acrylamide
Template:Chembox new
# Overview
The chemical compound acrylamide (acrylic amide) has the chemical formula C3H5NO. Its IUPAC name is 2-propenamide. It is a white odourless crystalline solid, soluble in water, ethanol, ether and chloroform. Acrylamide is incompatible with acids, bases, oxidizing agents, iron and iron salts. It decomposes non thermally to form ammonia and thermal decomposition produces carbon monoxide, carbon dioxide and oxides of nitrogen.
Most acrylamide is used to synthesize polyacrylamides which find many uses as water-soluble thickeners. These include use in wastewater treatment, gel electrophoresis (SDS-PAGE), papermaking, ore processing, and the manufacture of permanent press fabrics. Some acrylamide is used in the manufacture of dyes and the manufacture of other monomers.
Acrylamide was accidentally discovered in foods in April 2002 by scientists in Sweden when they found large amounts of the chemical in starchy foods, such as potato chips, French fries, and bread. It is not found in food which has been boiled.[1]
# Occurrence in daily life
Acrylamide in fried or baked goods is produced by the reaction between asparagine and reducing sugars (fructose, glucose, etc.) or reactive carbonyls. Acrylamide in olives and prune juice comes through another process. It has been suggested that environmental pathways, such as the breakdown of the herbicide glyphosate (Roundup), are sources too. Smoking is also a major acrylamide producer. Estimates for the proportion in the diet coming from the consumption of coffee range from twenty to forty percent. Acrylamide cannot be created by boiling, and very few uncooked foods contain any detectable amounts. Browning during baking, frying or deep-frying will produce acrylamide and over-cooking of foods will produce large amounts of acrylamide. Acrylamides can also be created during microwaving.
# Reduction of acrylamide formation
## Storage
In the case of potatoes for instance the storage temperature should not drop below 8°C. When the temperature is as low as 4°C the fructose content rises sharply, so that the acrylamide formation during baking or deep-frying will be higher.
## Raw Material
New varieties of potatoes are being bred that produce less or no acrylamide.
## Production methods
In many cases it is advisable to lower the maximum temperature during baking. Also new production methods such as vacuum frying may lower the acrylamide formation.
When silicone is used as a foam inhibitor in deep-frying fats in the food industry the acrylamide content is doubled.
## Recipe Formulation
Asparaginase, a naturally-occurring enzyme, can be added to bread or potato mixtures to reduce formation of acrylamide during cooking [2]
# Potential health risk
There is evidence that exposure to large doses can cause damage to the male reproductive glands. Direct exposure to pure acrylamide by inhalation, skin absorption, or eye contact irritates the exposed mucous membranes, e.g. the nose, and can also cause sweating, urinary incontinence, nausea, myalgia, speech disorders, numbness, paresthesia, and weakened legs and hands. In addition, the acrylamide monomer is a potent neurotoxin, causing the disassembly or rearrangement of intermediate filaments[3]. Ingested acrylamide is metabolised to a chemically reactive epoxide, glycidamide.[1]
## Cancer
According to a 2005 review[4], acrylamide reliably produces various types of cancer in experimental mice and rats. However, studies in human populations have failed to produce consistent results, and it remains unclear whether this is due to a reduced risk in a natural setting or the methodological difficulties inherent in such studies. For example, it might be difficult to isolate the effects of acrylamide because it is so ubiquitous in western diets.
## Public awareness
In 2002-04-24 the Swedish National Food Administration (Livsmedelsverket) announced that acrylamide can be found in baked and fried starchy foods, such as potato chips, breads and cookies. Concern was raised mainly because of the carcinogenic effects of acrylamide. This was followed by a strong but short-lived interest from the press. On 2005-08-26, California attorney general Bill Lockyer filed a lawsuit against top makers of french fries and potato chips to warn consumers of the potential risk from consuming acrylamide. [2] | https://www.wikidoc.org/index.php/Acrylamide | |
0dc51e8d3816f4f96b9ac5ec644290d23311779b | wikidoc | Actigraphy | Actigraphy
# Overview
Actigraphy is a method of activity and sleep study achieved by mounting a small actigraph unit on a patient for an extended period of time. The unit itself typically includes a small accelerometer and continually records the movements it undergoes. When the data is later read to a computer it can be analysed and used in the study of circadian rhythm and wake-sleep patterns.
It usually involves subjects to wear an actigraph to measure gross motor activity. Motor activity usually under test is that of the wrist, measured by an actigraph in a wrist-watch-like package. Actigraphs measure day-to-day activity of an individual, recording movement being made during waking and sleeping hours.
Actigraphy is useful for assessing daytime sleepiness in situations where a laboratory sleep latency test is not appropriate. Actigraphy is used to clinically evaluate insomnia, circadian rhythm sleep disorders, excessive sleepiness and restless leg syndrome. It is also used in the assessing of the effectiveness of pharmacologic, behavioural, phototherapeutic or chronotherapeutic treatments for these disorders.
Actigraphy has not traditionally been used in routine diagnosis of sleep disorders but is increasingly being employed in sleep clinics to replace full polysomnography. The technique is much more extensively used in academic research and is being increasingly employed in new drug clinical trials where sleep quality is seen as a good indicator of quality of life.
Models of Actigraphs vary widely in size and features and can be expanded to include sensors which monitor light, sound, temperature, parkinsonian tremor, allow for subjective user input or which allow for the recording of a full EEG data stream. | Actigraphy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Actigraphy is a method of activity and sleep study achieved by mounting a small actigraph unit on a patient for an extended period of time. The unit itself typically includes a small accelerometer and continually records the movements it undergoes. When the data is later read to a computer it can be analysed and used in the study of circadian rhythm and wake-sleep patterns.
It usually involves subjects to wear an actigraph to measure gross motor activity. Motor activity usually under test is that of the wrist, measured by an actigraph in a wrist-watch-like package. Actigraphs measure day-to-day activity of an individual, recording movement being made during waking and sleeping hours.
Actigraphy is useful for assessing daytime sleepiness in situations where a laboratory sleep latency test is not appropriate. Actigraphy is used to clinically evaluate insomnia, circadian rhythm sleep disorders, excessive sleepiness and restless leg syndrome. It is also used in the assessing of the effectiveness of pharmacologic, behavioural, phototherapeutic or chronotherapeutic treatments for these disorders.
Actigraphy has not traditionally been used in routine diagnosis of sleep disorders but is increasingly being employed in sleep clinics to replace full polysomnography. The technique is much more extensively used in academic research and is being increasingly employed in new drug clinical trials where sleep quality is seen as a good indicator of quality of life.
Models of Actigraphs vary widely in size and features and can be expanded to include sensors which monitor light, sound, temperature, parkinsonian tremor, allow for subjective user input or which allow for the recording of a full EEG data stream.
# External links
- American Academy of Sleep Medicine - Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: An update for 2002
Template:WS | https://www.wikidoc.org/index.php/Actigraph | |
82c72340a02cab6ddeaf9de14570074257f8b2d9 | wikidoc | Acting out | Acting out
# Overview
Acting out is a psychological term meaning to perform an action to express (often subconscious) emotional conflicts. The acting done is usually anti-social and may take the form of acting on the impulses of an addiction (eg. drinking, drug taking or shoplifting) or in a means designed (often unconsciously or semi-consciously) to garner attention (eg. throwing a tantrum or behaving promiscuously).
The action performed is usually destructive to self or others and may inhibit the development of more constructive responses to the feelings. The term is used in sexual addiction treatment, psychotherapy, criminology and parenting.
Acting out painful feelings may be contrasted with expressing them in ways more helpful to the sufferer, e.g. by talking cure| talking out, expressive therapy, psychodrama or mindfulness| mindful awareness of the feelings. Developing the ability to express one's conflicts safely and constructively is an important part of impulse control, personal development and self-care. | Acting out
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Acting out is a psychological term meaning to perform an action to express (often subconscious) emotional conflicts. The acting done is usually anti-social and may take the form of acting on the impulses of an addiction (eg. drinking, drug taking or shoplifting) or in a means designed (often unconsciously or semi-consciously) to garner attention (eg. throwing a tantrum or behaving promiscuously).
The action performed is usually destructive to self or others and may inhibit the development of more constructive responses to the feelings. The term is used in sexual addiction treatment, psychotherapy, criminology and parenting.
Acting out painful feelings may be contrasted with expressing them in ways more helpful to the sufferer, e.g. by talking cure| talking out, expressive therapy, psychodrama or mindfulness| mindful awareness of the feelings. Developing the ability to express one's conflicts safely and constructively is an important part of impulse control, personal development and self-care. | https://www.wikidoc.org/index.php/Acting_out | |
516e1c9568d07d229181e830082ccddfb36cdecb | wikidoc | Ketoprofen | Ketoprofen
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ketoprofen is a analgesic, anti-inflammatory, antimigraine, antirheumatic, central nervous system agent and musculoskeletal agent that is FDA approved for the treatment of rheumatoid arthritis, osteoarthritis, pain and dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, rash, abdominal pain, constipation, diarrhea, flatulence, indigestion, nausea, increased liver function test, CNS depression, CNS stimulation, dizziness, headache, abnormal vision, tinnitus and renal impairment..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 75 mg PO q8h or 50 mg PO q6h
- The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.
- Dosage: 75 mg PO q8h or 50 mg PO q6h
- The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.
- Dosage: 25 to 50 mg every 6 to 8 hours as necessary. A larger dose may be tried if the patient’s response to a previous dose was less than satisfactory, but doses above 75 mg have not been shown to give added analgesia.
- Dosage: 12.5 mg q4h-q6h
Maximum dose: 75 mg/day (six 12.5mg tablets)
- Maximum dose: 75 mg/day (six 12.5mg tablets)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketoprofen in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA doesn't indicate Ketoprofen for patients under 18 years old
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ketoprofen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketoprofen in pediatric patients.
# Contraindications
- Ketoprofen immediate- and extended-release capsules should not be given to patients who have experienced asthma, urticaria, or allergic type reactions after taking aspirin or other NSAIDs.
- Ketoprofen immediate- and extended-release capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft.
# Warnings
### Cardiovascular Effects
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- NSAIDs, including ketoprofen capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. ], including ketoprofen capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Fluid retention and edema have been observed in some patients taking NSAIDs. Peripheral edema has been observed in approximately 2% of patients taking ketoprofen. Ketoprofen capsules should be used with caution in patients with fluid retention or heart failure.
### Gastrointestinal Effects
- NSAIDs, including ketoprofen capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
### Renal Effects
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- No information is available from controlled clinical studies regarding the use of ketoprofen capsules in patients with advanced renal disease. Therefore, treatment with ketoprofen capsules is not recommended in these patients with advanced renal disease. If ketoprofen capsule therapy must be initiated, close monitoring of the patient's renal function is advisable.
### Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketoprofen capsules. Ketoprofen capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
### Skin Reactions
- NSAIDs, including ketoprofen capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
### Pregnancy
In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.
# Adverse Reactions
## Clinical Trials Experience
### Incidence > 1% with Probable Causal Relationship
- Dyspepsia
- Nausea
- Abdominal pain
- Diarrhea
- Constipation
- Flatulence
- Anorexia
- Vomiting
- Stomatitis
- Headache
- Dizziness
- CNS inhibition: somnolence, malaise and depression.
- CNS excitation: insomnia and nervousness
- Tinnitus
- Visual disturbances
- Rash
- Renal impairment
- Urinary Tract Infections (UTI's)
### Incidence < 1% with Probable Causal Relationship
- Chills
- Facial edema
- Infections
- Pain
- Anaphylaxis
- Hypertension
- Palpitations
- Tachycardia
- Congestive Heart Failure (CHF)
- Peripheral vascular disease
- Vasodilation
- Appetite increased
- Dry mouth
- Eructation
- Gastritis
- Rectal hemorrhage
- Melena
- Fecal occult blood
- Salivation
- Peptic ulcer,
- Gastrointestinal perforation
- Hematemesis
- Intestinal ulceration
- Hepatic dysfunction
- Hepatitis
- Cholestatic hepatitis
- Jaundice
- Hypocoagulability
- Agranulocytosis
- Anemia
- Hemolysis
- Purpura
- Thrombocytopenia
- Thirst
- Weight gain
- Weight loss
- Hyponatremia
- Myalgia
- Amnesia
- Confusion
- Impotence
- Migraine
- Paresthesia
- Vertigo
- Dyspnea
- Hemoptysis
- Epistaxis
- Pharyngitis
- Rhinitis
- Bronchospasm
- Laryngeal edema
- Alopecia
- Eczema
- Pruritus
- Purpuric rash
- Sweating
- Urticaria
- Bullous rash
- Exfoliative dermatitis
- Photosensitivity
- Skin discoloration
- Onycholysis
- Toxic epidermal necrolysis
- Erythema multiforme
- Stevens-Johnson syndrome
- Conjunctivitis
- Conjunctivitis sicca
- Eye pain
- Hearing impairment
- Retinal hemorrhage and pigmentation change
- Taste perversion
- Menometrorrhagia
- Hematuria
- Renal failure
- Interstitial nephritis
- Nephrotic syndrome
### Incidence < 1% with Unknown Causal Relationship
- Septicemia
- Shock
- Arrhythmia
- Myocardial infarction
- Buccal necrosis
- Ulcerative colitis
- Microvesicular steatosis
- Pancreatitis
- Diabetes Mellitus
- Dysphoria
- Hallucination
- Libido disturbance
- Nightmares
- Personality disorder
- Aseptic meningitis
- Acute tubulopathy
- Gynecomastia
## Postmarketing Experience
There is limited information regarding Ketoprofen Postmarketing Experience in the drug label.
# Drug Interactions
### Drug Interactions
The following drug interactions were studied with ketoprofen doses of 200 mg/day. The possibility of increased interaction should be kept in mind when ketoprofen capsule doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs.
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
- Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as ketoprofen capsules.
- Ketoprofen does not alter aspirin absorption; however, in a study of 12 normal subjects, concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0.07 L/kg/h without aspirin to 0.11 L/kg/h with aspirin. The clinical significance of these changes is not known; however, as with other NSAIDs, concomitant administration of ketoprofen and aspirin is not generally recommended because of the potential of increased adverse effects.
- NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone. Patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered, ketoprofen did not alter the serum levels of digoxin.
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Ketoprofen, like other NSAIDs, may cause changes in the elimination of methotrexate leading to elevated serum levels of the drug and increased toxicity. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen to about one-third, as well as decreasing its protein binding. Therefore, the combination of ketoprofen and probenecid is not recommended.
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. In a short-term controlled study in 14 normal volunteers, ketoprofen did not significantly interfere with the effect of warfarin on prothrombin time. Bleeding from a number of sites may be a complication of warfarin treatment and GI bleeding a complication of ketoprofen treatment. Because prostaglandins play an important role in hemostasis and ketoprofen has an effect on platelet function as well, concurrent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- In teratology studies ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m2/day) and rats at doses up to 9 mg/kg/day (54 mg/m2/day), the approximate equivalent of 0.2 times the maximum recommended therapeutic dose of 185 mg/m2/day, showed no teratogenic or embryotoxic effects. In separate studies in rabbits, maternally toxic doses were associated with embryotoxicity but not teratogenicity. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Ketoprofen capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ketoprofen in women who are pregnant.
### Labor and Delivery
- The effects of ketoprofen on labor and delivery in pregnant women are unknown. Studies in rats have shown ketoprofen at doses of 6 mg/kg (36 mg/m2/day, approximately equal to 0.2 times the maximum recommended human dose) prolongs pregnancy when given before the onset of labor. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), use of ketoprofen during late pregnancy should be avoided.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Data on secretion in human milk after ingestion of ketoprofen do not exist. In rats, ketoprofen at doses of 9 mg/kg (54 mg/m2/day; approximately 0.3 times the maximum human therapeutic dose) did not affect perinatal development. Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of the plasma drug level. As with other drugs that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.
### Geriatic Use
- As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). In pharmacokinetic studies, ketoprofen clearance was reduced in older patients receiving ketoprofen capsules, compared with younger patients. Peak ketoprofen concentrations and free drug AUC were increased in older patients. The glucuronide conjugate of ketoprofen, which can serve as a potential reservoir for the parent drug, is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. It is recommended that the initial dosage of ketoprofen capsules should be reduced for patients over 75 years of age and it may be useful to monitor renal function. In addition, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients. In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Therefore, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose.
- In ketoprofen capsule clinical studies involving a total of 1540 osteoarthritis or rheumatoid arthritis patients, 369 (24%) were ≥ 65 years of age, and 92 (6%) were ≥ 75 years of age. For ketoprofen capsule acute pain studies, 23 (5%) of 484 patients were ≥ 60 years of age. No overall differences in effectiveness were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Ketoprofen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ketoprofen with respect to specific racial populations.
### Renal Impairment
- Studies of the effects of renal-function impairment have been small. They indicate a decrease in clearance in patients with impaired renal function. In 23 patients with renal impairment, free ketoprofen peak concentration was not significantly elevated, but free ketoprofen clearance was reduced from 15 L/kg/h for normal subjects to 7 L/kg/h in patients with mildly impaired renal function, and to 4 L/kg/h in patients with moderately to severely impaired renal function. The elimination t1/2 was prolonged from 1.6 hours in normal subjects to approximately 3 hours in patients with mild renal impairment, and to approximately 5 to 9 hours in patients with moderately to severely impaired renal function.
### Hepatic Impairment
- For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of immediate-release ketoprofen capsules were observed relative to age-matched normal subjects: the plasma clearance of drug was 0.07 L/kg/h in 26 hepatically impaired patients. The elimination half-life was comparable to that observed for normal subjects. However, the unbound (biologically active) fraction was approximately doubled, probably due to hypoalbuminemia and high variability which was observed in the pharmacokinetics for cirrhotic patients. Therefore, these patients should be carefully monitored and daily doses of ketoprofen kept at the minimum providing the desired therapeutic effect.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ketoprofen in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ketoprofen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ketoprofen Administration in the drug label.
### Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, ketoprofen capsules should be discontinued.
# IV Compatibility
There is limited information regarding the compatibility of Ketoprofen and IV administrations.
# Overdosage
- Signs and symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Respiratory depression, coma, or convulsions have occurred following large ketoprofen overdoses. Gastrointestinal bleeding, hypotension, hypertension, or acute renal failure may occur, but are rare.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients with symptoms seen within 4 hours or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with a saline cathartic or sorbitol added to the first dose. Forced diuresis, alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to ketoprofen’s high protein binding.
Case reports include twenty-six overdoses: 6 were in children, 16 in adolescents, and 4 in adults. Five of these patients had minor symptoms (vomiting in 4, drowsiness in 1 child). A 12-year-old girl had tonic-clonic convulsions 1 to 2 hours after ingesting an unknown quantity of ketoprofen and 1 or 2 tablets of acetaminophen with hydrocodone. Her ketoprofen level was 1128 mg/L (56 times the upper therapeutic level of 20 mg/L) 3 to 4 hours post ingestion. Full recovery ensued 18 hours after ingestion following management with intubation, diazepam, and activated charcoal. A 45-year-old woman ingested twelve 200 mg extended-release ketoprofen capsules and 375 mL vodka, was treated with emesis and supportive measures 2 hours after ingestion, and recovered completely with her only complaint being mild epigastric pain.
# Pharmacology
## Mechanism of Action
The anti-inflammatory, analgesic and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro test systems. In anti-inflammatory models ketoprofen has been shown to have inhibitory effects on prostaglandin and leukotriene synthesis, to have antibradykinin activity, as well as to have lysosomal membrane-stabilizing action. However, its mode of action, like that of other non-steroidal anti-inflammatory drugs, is not fully understood.
## Structure
- Ketoprofen is a non-steroidal anti-inflammatory drug. The chemical name for ketoprofen is 2-(3-benzoylphenyl)-propionic acid with the following structural formula:
- It has a pKa of 5.94 in methanol: water (3:1) and an n-octanol: water partition coefficient of 0.97 (buffer pH 7.4).
- Ketoprofen is a white or off-white, odorless, nonhygroscopic, fine to granular powder, melting at about 95°C. It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong alkali, but practically insoluble in water at 20°C.
## Pharmacodynamics
- Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The enantiomers have similar concentration time curves and do not appear to interact with one another.
- An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain study with immediate-release ketoprofen capsules. The effect-site rate constant (ke0) was estimated to be 0.9 hour-1 (95% confidence limits: 0 to 2.1), and the concentration (Ce50) of ketoprofen that produced one-half the maximum PID (pain intensity difference) was 0.3 mcg/mL (95% confidence limits: 0.1 to 0.5). Thirty-three (33) to 68% of patients had an onset of action (as measured by reporting some pain relief) within 30 minutes following a single oral dose in postoperative pain and dysmenorrhea studies. Pain relief (as measured by remedication) persisted for up to 6 hours in 26 to 72% of patients in these studies.
## Pharmacokinetics
### General
- The systemic availability (FS) when the oral formulation is compared with IV administration is approximately 90% in humans. For 75 to 200 mg single doses, the area under the curve has been shown to be dose proportional.
- Ketoprofen is > 99% bound to plasma proteins, mainly to albumin.
### Absorption
- Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0.5 to 2 hours.
- When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed.
- Food intake reduces Cmax by approximately one-half and increases the mean time to peak concentration (tmax) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian changes in the absorption process.
- Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen from ketoprofen capsules.
### Multiple Dosing
Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with immediate-release ketoprofen capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of immediate-release ketoprofen 50 mg capsules QID for 12 hours were 0.07 mg/L and 0.13 mg/L at 24 hours following administration of immediate-release ketoprofen 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of immediate-release ketoprofen capsules is minimal.
The figure below shows a reduction in peak height and area after the second 50 mg dose. This is probably due to a combination of food effects, circadian effects, and plasma sampling times. It is unclear to what extent each factor contributes to the loss of peak height and area.
(The shaded area represents ± 1 standard deviation (S.D.) around the mean for immediate-release ketoprofen capsules).
### Metabolism
The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug, and this may be important in persons with renal insufficiency, whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent drug. The conjugates are reported to appear only in trace amounts in plasma in healthy adults, but are higher in elderly subjects-presumably because of reduced renal clearance. It has been demonstrated that in elderly subjects following multiple doses (50 mg every 6 h), the ratio of conjugated to parent ketoprofen AUC was 30% and 3%, respectively, for the S & R enantiomers. There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug-metabolizing enzymes.
### Elimination
- The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vd of 0.1 L/kg after IV administration. The elimination half-life of ketoprofen has been reported to be 2.05 ± 0.58 h (Mean ± S.D.) following IV administration from 2 to 4 hours following administration of ketoprofen capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus t1/2 relative to an IV dose appears prolonged.
- In a 24 hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine, primarily as the glucuronide metabolite.
- Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been measured to confirm this.
### Special Populations
The plasma and renal clearance of ketoprofen is reduced in the elderly (mean age, 73 years) compared to a younger normal population (mean age, 27 years). Hence, ketoprofen peak concentration and AUC increase with increasing age. In addition, there is a corresponding increase in unbound fraction with increasing age. Data from one trial suggest that the increase is greater in women than in men. It has not been determined whether age-related changes in absorption among the elderly contribute to the changes in bioavailability of ketoprofen.
In a study conducted with young and elderly men and women, results for subjects older than 75 years of age showed that free drug AUC increased by 40% and Cmax increased by 60% as compared with estimates of the same parameters in young subjects (those younger than 35 years of age.
Also in the elderly, the ratio of intrinsic clearance/availability decreased by 35% and plasma half-life was prolonged by 26%. This reduction is thought to be due to a decrease in hepatic extraction associated with aging.
## Nonclinical Toxicology
There is limited information regarding Ketoprofen Nonclinical Toxicology in the drug label.
# Clinical Studies
### Rheumatoid Arthritis and Osteoarthritis
- The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac, and indomethacin. In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs.
- In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control non-steroidal drugs.
### Management of Pain
- The effectiveness of immediate-release ketoprofen capsules as a general-purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 to 150 mg. Doses of 25 mg were superior to placebo. Doses larger than 25 mg generally could not be shown to be significantly more effective, but there was a tendency toward faster onset and greater duration of action with 50 mg, and, in the case of dysmenorrhea, a significantly greater effect overall with 75 mg. Doses greater than 50 to 75 mg did not have increased analgesic effect. Studies in postoperative pain have shown that ketoprofen in doses of 25 to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of acetaminophen with 10 mg of oxycodone. Ketoprofen tended to be somewhat slower in onset; peak pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer, particularly with the higher doses of ketoprofen.
# How Supplied
Ketoprofen capsules are available as follows:
- 50 mg: Blue cap and light blue body, imprinted “93” over "3193" on the cap and on the body, in bottles of 100.
- 75 mg: Blue cap and white body, imprinted “TEVA” on the cap and “3195” on the body, in bottles of 100 and 500.
## Storage
- Store at 20° to 25°C (68° to 77°F) . Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ketoprofen Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Ketoprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orudis
- Orudis KT
- Oruvail
# Look-Alike Drug Names
There is limited information regarding Ketoprofen Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ketoprofen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Black Box Warning
# Overview
Ketoprofen is a analgesic, anti-inflammatory, antimigraine, antirheumatic, central nervous system agent and musculoskeletal agent that is FDA approved for the treatment of rheumatoid arthritis, osteoarthritis, pain and dysmenorrhea. There is a Black Box Warning for this drug as shown here. Common adverse reactions include edema, rash, abdominal pain, constipation, diarrhea, flatulence, indigestion, nausea, increased liver function test, CNS depression, CNS stimulation, dizziness, headache, abnormal vision, tinnitus and renal impairment..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosage: 75 mg PO q8h or 50 mg PO q6h
- The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.
- Dosage: 75 mg PO q8h or 50 mg PO q6h
- The recommended maximum daily dose of ketoprofen capsules is 300 mg/day.
- Dosage: 25 to 50 mg every 6 to 8 hours as necessary. A larger dose may be tried if the patient’s response to a previous dose was less than satisfactory, but doses above 75 mg have not been shown to give added analgesia.
- Dosage: 12.5 mg q4h-q6h
Maximum dose: 75 mg/day (six 12.5mg tablets)
- Maximum dose: 75 mg/day (six 12.5mg tablets)
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults [1]
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketoprofen in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA doesn't indicate Ketoprofen for patients under 18 years old
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ketoprofen in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ketoprofen in pediatric patients.
# Contraindications
- Ketoprofen immediate- and extended-release capsules should not be given to patients who have experienced asthma, urticaria, or allergic type reactions after taking aspirin or other NSAIDs.
- Ketoprofen immediate- and extended-release capsules are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft.
# Warnings
### Cardiovascular Effects
- Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.
- There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10 to 14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- NSAIDs, including ketoprofen capsules, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. [NSAIDs]], including ketoprofen capsules, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.
- Fluid retention and edema have been observed in some patients taking NSAIDs. Peripheral edema has been observed in approximately 2% of patients taking ketoprofen. Ketoprofen capsules should be used with caution in patients with fluid retention or heart failure.
### Gastrointestinal Effects
- NSAIDs, including ketoprofen capsules, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
- NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
- To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
### Renal Effects
- Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a non-steroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE-inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.
- No information is available from controlled clinical studies regarding the use of ketoprofen capsules in patients with advanced renal disease. Therefore, treatment with ketoprofen capsules is not recommended in these patients with advanced renal disease. If ketoprofen capsule therapy must be initiated, close monitoring of the patient's renal function is advisable.
### Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to ketoprofen capsules. Ketoprofen capsules should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs. Emergency help should be sought in cases where an anaphylactoid reaction occurs.
### Skin Reactions
- NSAIDs, including ketoprofen capsules, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.
### Pregnancy
In late pregnancy, as with other NSAIDs, ketoprofen capsules should be avoided because they may cause premature closure of the ductus arteriosus.
# Adverse Reactions
## Clinical Trials Experience
### Incidence > 1% with Probable Causal Relationship
- Dyspepsia
- Nausea
- Abdominal pain
- Diarrhea
- Constipation
- Flatulence
- Anorexia
- Vomiting
- Stomatitis
- Headache
- Dizziness
- CNS inhibition: somnolence, malaise and depression.
- CNS excitation: insomnia and nervousness
- Tinnitus
- Visual disturbances
- Rash
- Renal impairment
- Urinary Tract Infections (UTI's)
### Incidence < 1% with Probable Causal Relationship
- Chills
- Facial edema
- Infections
- Pain
- Anaphylaxis
- Hypertension
- Palpitations
- Tachycardia
- Congestive Heart Failure (CHF)
- Peripheral vascular disease
- Vasodilation
- Appetite increased
- Dry mouth
- Eructation
- Gastritis
- Rectal hemorrhage
- Melena
- Fecal occult blood
- Salivation
- Peptic ulcer,
- Gastrointestinal perforation
- Hematemesis
- Intestinal ulceration
- Hepatic dysfunction
- Hepatitis
- Cholestatic hepatitis
- Jaundice
- Hypocoagulability
- Agranulocytosis
- Anemia
- Hemolysis
- Purpura
- Thrombocytopenia
- Thirst
- Weight gain
- Weight loss
- Hyponatremia
- Myalgia
- Amnesia
- Confusion
- Impotence
- Migraine
- Paresthesia
- Vertigo
- Dyspnea
- Hemoptysis
- Epistaxis
- Pharyngitis
- Rhinitis
- Bronchospasm
- Laryngeal edema
- Alopecia
- Eczema
- Pruritus
- Purpuric rash
- Sweating
- Urticaria
- Bullous rash
- Exfoliative dermatitis
- Photosensitivity
- Skin discoloration
- Onycholysis
- Toxic epidermal necrolysis
- Erythema multiforme
- Stevens-Johnson syndrome
- Conjunctivitis
- Conjunctivitis sicca
- Eye pain
- Hearing impairment
- Retinal hemorrhage and pigmentation change
- Taste perversion
- Menometrorrhagia
- Hematuria
- Renal failure
- Interstitial nephritis
- Nephrotic syndrome
### Incidence < 1% with Unknown Causal Relationship
- Septicemia
- Shock
- Arrhythmia
- Myocardial infarction
- Buccal necrosis
- Ulcerative colitis
- Microvesicular steatosis
- Pancreatitis
- Diabetes Mellitus
- Dysphoria
- Hallucination
- Libido disturbance
- Nightmares
- Personality disorder
- Aseptic meningitis
- Acute tubulopathy
- Gynecomastia
## Postmarketing Experience
There is limited information regarding Ketoprofen Postmarketing Experience in the drug label.
# Drug Interactions
### Drug Interactions
The following drug interactions were studied with ketoprofen doses of 200 mg/day. The possibility of increased interaction should be kept in mind when ketoprofen capsule doses greater than 50 mg as a single dose or 200 mg of ketoprofen per day are used concomitantly with highly bound drugs.
- Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking NSAIDs concomitantly with ACE-inhibitors.
- Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with the rate or extent of the absorption of ketoprofen administered as ketoprofen capsules.
- Ketoprofen does not alter aspirin absorption; however, in a study of 12 normal subjects, concurrent administration of aspirin decreased ketoprofen protein binding and increased ketoprofen plasma clearance from 0.07 L/kg/h without aspirin to 0.11 L/kg/h with aspirin. The clinical significance of these changes is not known; however, as with other NSAIDs, concomitant administration of ketoprofen and aspirin is not generally recommended because of the potential of increased adverse effects.
- NSAIDs can reduce the natriuretic effect of furosemide and thiazides in some patients. Hydrochlorothiazide, given concomitantly with ketoprofen, produces a reduction in urinary potassium and chloride excretion compared to hydrochlorothiazide alone. Patients taking diuretics are at a greater risk of developing renal failure secondary to a decrease in renal blood flow caused by prostaglandin inhibition. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure, as well as to assure diuretic efficacy.
- In a study in 12 patients with congestive heart failure where ketoprofen and digoxin were concomitantly administered, ketoprofen did not alter the serum levels of digoxin.
- NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%. These effects have been attributed to inhibition of renal prostaglandin synthesis by the NSAID. Thus, when NSAIDs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Ketoprofen, like other NSAIDs, may cause changes in the elimination of methotrexate leading to elevated serum levels of the drug and increased toxicity. NSAIDs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when NSAIDs are administered concomitantly with methotrexate.
- Probenecid increases both free and bound ketoprofen by reducing the plasma clearance of ketoprofen to about one-third, as well as decreasing its protein binding. Therefore, the combination of ketoprofen and probenecid is not recommended.
- The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. In a short-term controlled study in 14 normal volunteers, ketoprofen did not significantly interfere with the effect of warfarin on prothrombin time. Bleeding from a number of sites may be a complication of warfarin treatment and GI bleeding a complication of ketoprofen treatment. Because prostaglandins play an important role in hemostasis and ketoprofen has an effect on platelet function as well, concurrent therapy with ketoprofen and warfarin requires close monitoring of patients on both drugs.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- In teratology studies ketoprofen administered to mice at doses up to 12 mg/kg/day (36 mg/m2/day) and rats at doses up to 9 mg/kg/day (54 mg/m2/day), the approximate equivalent of 0.2 times the maximum recommended therapeutic dose of 185 mg/m2/day, showed no teratogenic or embryotoxic effects. In separate studies in rabbits, maternally toxic doses were associated with embryotoxicity but not teratogenicity. However, animal reproduction studies are not always predictive of human response. There are no adequate and well-controlled studies in pregnant women. Ketoprofen capsules should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ketoprofen in women who are pregnant.
### Labor and Delivery
- The effects of ketoprofen on labor and delivery in pregnant women are unknown. Studies in rats have shown ketoprofen at doses of 6 mg/kg (36 mg/m2/day, approximately equal to 0.2 times the maximum recommended human dose) prolongs pregnancy when given before the onset of labor. Because of the known effects of prostaglandin-inhibiting drugs on the fetal cardiovascular system (closure of ductus arteriosus), use of ketoprofen during late pregnancy should be avoided.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Data on secretion in human milk after ingestion of ketoprofen do not exist. In rats, ketoprofen at doses of 9 mg/kg (54 mg/m2/day; approximately 0.3 times the maximum human therapeutic dose) did not affect perinatal development. Upon administration to lactating dogs, the milk concentration of ketoprofen was found to be 4 to 5% of the plasma drug level. As with other drugs that are excreted in milk, ketoprofen is not recommended for use in nursing mothers.
### Pediatric Use
- Safety and effectiveness in pediatric patients below the age of 18 have not been established.
### Geriatic Use
- As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older). In pharmacokinetic studies, ketoprofen clearance was reduced in older patients receiving ketoprofen capsules, compared with younger patients. Peak ketoprofen concentrations and free drug AUC were increased in older patients. The glucuronide conjugate of ketoprofen, which can serve as a potential reservoir for the parent drug, is known to be substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. It is recommended that the initial dosage of ketoprofen capsules should be reduced for patients over 75 years of age and it may be useful to monitor renal function. In addition, the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients may be more sensitive to the antiprostaglandin effects of NSAIDs (on the gastrointestinal tract and kidneys) than younger patients. In particular, elderly or debilitated patients who receive NSAID therapy seem to tolerate gastrointestinal ulceration or bleeding less well than other individuals, and most spontaneous reports of fatal GI events are in this population. Therefore, caution should be exercised in treating the elderly, and when individualizing their dosage, extra care should be taken when increasing the dose.
- In ketoprofen capsule clinical studies involving a total of 1540 osteoarthritis or rheumatoid arthritis patients, 369 (24%) were ≥ 65 years of age, and 92 (6%) were ≥ 75 years of age. For ketoprofen capsule acute pain studies, 23 (5%) of 484 patients were ≥ 60 years of age. No overall differences in effectiveness were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Ketoprofen with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ketoprofen with respect to specific racial populations.
### Renal Impairment
- Studies of the effects of renal-function impairment have been small. They indicate a decrease in clearance in patients with impaired renal function. In 23 patients with renal impairment, free ketoprofen peak concentration was not significantly elevated, but free ketoprofen clearance was reduced from 15 L/kg/h for normal subjects to 7 L/kg/h in patients with mildly impaired renal function, and to 4 L/kg/h in patients with moderately to severely impaired renal function. The elimination t1/2 was prolonged from 1.6 hours in normal subjects to approximately 3 hours in patients with mild renal impairment, and to approximately 5 to 9 hours in patients with moderately to severely impaired renal function.
### Hepatic Impairment
- For patients with alcoholic cirrhosis, no significant changes in the kinetic disposition of immediate-release ketoprofen capsules were observed relative to age-matched normal subjects: the plasma clearance of drug was 0.07 L/kg/h in 26 hepatically impaired patients. The elimination half-life was comparable to that observed for normal subjects. However, the unbound (biologically active) fraction was approximately doubled, probably due to hypoalbuminemia and high variability which was observed in the pharmacokinetics for cirrhotic patients. Therefore, these patients should be carefully monitored and daily doses of ketoprofen kept at the minimum providing the desired therapeutic effect.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ketoprofen in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ketoprofen in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ketoprofen Administration in the drug label.
### Monitoring
- Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, ketoprofen capsules should be discontinued.
# IV Compatibility
There is limited information regarding the compatibility of Ketoprofen and IV administrations.
# Overdosage
- Signs and symptoms following acute NSAID overdose are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Respiratory depression, coma, or convulsions have occurred following large ketoprofen overdoses. Gastrointestinal bleeding, hypotension, hypertension, or acute renal failure may occur, but are rare.
Patients should be managed by symptomatic and supportive care following an NSAID overdose. There are no specific antidotes. Gut decontamination may be indicated in patients with symptoms seen within 4 hours or following a large overdose (5 to 10 times the usual dose). This should be accomplished via emesis and/or activated charcoal (60 to 100 g in adults, 1 to 2 g/kg in children) with a saline cathartic or sorbitol added to the first dose. Forced diuresis, alkalinization of the urine, hemodialysis or hemoperfusion would probably not be useful due to ketoprofen’s high protein binding.
Case reports include twenty-six overdoses: 6 were in children, 16 in adolescents, and 4 in adults. Five of these patients had minor symptoms (vomiting in 4, drowsiness in 1 child). A 12-year-old girl had tonic-clonic convulsions 1 to 2 hours after ingesting an unknown quantity of ketoprofen and 1 or 2 tablets of acetaminophen with hydrocodone. Her ketoprofen level was 1128 mg/L (56 times the upper therapeutic level of 20 mg/L) 3 to 4 hours post ingestion. Full recovery ensued 18 hours after ingestion following management with intubation, diazepam, and activated charcoal. A 45-year-old woman ingested twelve 200 mg extended-release ketoprofen capsules and 375 mL vodka, was treated with emesis and supportive measures 2 hours after ingestion, and recovered completely with her only complaint being mild epigastric pain.
# Pharmacology
## Mechanism of Action
The anti-inflammatory, analgesic and antipyretic properties of ketoprofen have been demonstrated in classical animal and in vitro test systems. In anti-inflammatory models ketoprofen has been shown to have inhibitory effects on prostaglandin and leukotriene synthesis, to have antibradykinin activity, as well as to have lysosomal membrane-stabilizing action. However, its mode of action, like that of other non-steroidal anti-inflammatory drugs, is not fully understood.
## Structure
- Ketoprofen is a non-steroidal anti-inflammatory drug. The chemical name for ketoprofen is 2-(3-benzoylphenyl)-propionic acid with the following structural formula:
- It has a pKa of 5.94 in methanol: water (3:1) and an n-octanol: water partition coefficient of 0.97 (buffer pH 7.4).
- Ketoprofen is a white or off-white, odorless, nonhygroscopic, fine to granular powder, melting at about 95°C. It is freely soluble in ethanol, chloroform, acetone, ether and soluble in benzene and strong alkali, but practically insoluble in water at 20°C.
## Pharmacodynamics
- Ketoprofen is a racemate with only the S enantiomer possessing pharmacological activity. The enantiomers have similar concentration time curves and do not appear to interact with one another.
- An analgesic effect-concentration relationship for ketoprofen was established in an oral surgery pain study with immediate-release ketoprofen capsules. The effect-site rate constant (ke0) was estimated to be 0.9 hour-1 (95% confidence limits: 0 to 2.1), and the concentration (Ce50) of ketoprofen that produced one-half the maximum PID (pain intensity difference) was 0.3 mcg/mL (95% confidence limits: 0.1 to 0.5). Thirty-three (33) to 68% of patients had an onset of action (as measured by reporting some pain relief) within 30 minutes following a single oral dose in postoperative pain and dysmenorrhea studies. Pain relief (as measured by remedication) persisted for up to 6 hours in 26 to 72% of patients in these studies.
## Pharmacokinetics
### General
- The systemic availability (FS) when the oral formulation is compared with IV administration is approximately 90% in humans. For 75 to 200 mg single doses, the area under the curve has been shown to be dose proportional.
- Ketoprofen is > 99% bound to plasma proteins, mainly to albumin.
### Absorption
- Ketoprofen is rapidly and well-absorbed, with peak plasma levels occurring within 0.5 to 2 hours.
- When ketoprofen is administered with food, its total bioavailability (AUC) is not altered; however, the rate of absorption is slowed.
- Food intake reduces Cmax by approximately one-half and increases the mean time to peak concentration (tmax) from 1.2 hours for fasting subjects (range, 0.5 to 3 hours) to 2.0 hours for fed subjects (range, 0.75 to 3 hours). The fluctuation of plasma peaks may also be influenced by circadian changes in the absorption process.
- Concomitant administration of magnesium hydroxide and aluminum hydroxide does not interfere with absorption of ketoprofen from ketoprofen capsules.
### Multiple Dosing
Steady-state concentrations of ketoprofen are attained within 24 hours after commencing treatment with immediate-release ketoprofen capsules. In studies with healthy male volunteers, trough levels at 24 hours following administration of immediate-release ketoprofen 50 mg capsules QID for 12 hours were 0.07 mg/L and 0.13 mg/L at 24 hours following administration of immediate-release ketoprofen 75 mg capsules TID for 12 hours. Thus, relative to the peak plasma concentration, the accumulation of ketoprofen after multiple doses of immediate-release ketoprofen capsules is minimal.
The figure below shows a reduction in peak height and area after the second 50 mg dose. This is probably due to a combination of food effects, circadian effects, and plasma sampling times. It is unclear to what extent each factor contributes to the loss of peak height and area.
(The shaded area represents ± 1 standard deviation (S.D.) around the mean for immediate-release ketoprofen capsules).
### Metabolism
The metabolic fate of ketoprofen is glucuronide conjugation to form an unstable acyl-glucuronide. The glucuronic acid moiety can be converted back to the parent compound. Thus, the metabolite serves as a potential reservoir for parent drug, and this may be important in persons with renal insufficiency, whereby the conjugate may accumulate in the serum and undergo deconjugation back to the parent drug. The conjugates are reported to appear only in trace amounts in plasma in healthy adults, but are higher in elderly subjects-presumably because of reduced renal clearance. It has been demonstrated that in elderly subjects following multiple doses (50 mg every 6 h), the ratio of conjugated to parent ketoprofen AUC was 30% and 3%, respectively, for the S & R enantiomers. There are no known active metabolites of ketoprofen. Ketoprofen has been shown not to induce drug-metabolizing enzymes.
### Elimination
- The plasma clearance of ketoprofen is approximately 0.08 L/kg/h with a Vd of 0.1 L/kg after IV administration. The elimination half-life of ketoprofen has been reported to be 2.05 ± 0.58 h (Mean ± S.D.) following IV administration from 2 to 4 hours following administration of ketoprofen capsules. In cases of slow drug absorption, the elimination rate is dependent on the absorption rate and thus t1/2 relative to an IV dose appears prolonged.
- In a 24 hour period, approximately 80% of an administered dose of ketoprofen is excreted in the urine, primarily as the glucuronide metabolite.
- Enterohepatic recirculation of the drug has been postulated, although biliary levels have never been measured to confirm this.
### Special Populations
The plasma and renal clearance of ketoprofen is reduced in the elderly (mean age, 73 years) compared to a younger normal population (mean age, 27 years). Hence, ketoprofen peak concentration and AUC increase with increasing age. In addition, there is a corresponding increase in unbound fraction with increasing age. Data from one trial suggest that the increase is greater in women than in men. It has not been determined whether age-related changes in absorption among the elderly contribute to the changes in bioavailability of ketoprofen.
In a study conducted with young and elderly men and women, results for subjects older than 75 years of age showed that free drug AUC increased by 40% and Cmax increased by 60% as compared with estimates of the same parameters in young subjects (those younger than 35 years of age.
Also in the elderly, the ratio of intrinsic clearance/availability decreased by 35% and plasma half-life was prolonged by 26%. This reduction is thought to be due to a decrease in hepatic extraction associated with aging.
## Nonclinical Toxicology
There is limited information regarding Ketoprofen Nonclinical Toxicology in the drug label.
# Clinical Studies
### Rheumatoid Arthritis and Osteoarthritis
- The efficacy of ketoprofen has been demonstrated in patients with rheumatoid arthritis and osteoarthritis. In other trials, ketoprofen demonstrated effectiveness comparable to aspirin, ibuprofen, naproxen, piroxicam, diclofenac, and indomethacin. In some of these studies there were more dropouts due to gastrointestinal side effects among patients on ketoprofen than among patients on other NSAIDs.
- In studies with patients with rheumatoid arthritis, ketoprofen was administered in combination with gold salts, antimalarials, low-dose methotrexate, d-penicillamine, and/or corticosteroids with results comparable to those seen with control non-steroidal drugs.
### Management of Pain
- The effectiveness of immediate-release ketoprofen capsules as a general-purpose analgesic has been studied in standard pain models which have shown the effectiveness of doses of 25 to 150 mg. Doses of 25 mg were superior to placebo. Doses larger than 25 mg generally could not be shown to be significantly more effective, but there was a tendency toward faster onset and greater duration of action with 50 mg, and, in the case of dysmenorrhea, a significantly greater effect overall with 75 mg. Doses greater than 50 to 75 mg did not have increased analgesic effect. Studies in postoperative pain have shown that ketoprofen in doses of 25 to 100 mg was comparable to 650 mg of acetaminophen with 60 mg of codeine, or 650 mg of acetaminophen with 10 mg of oxycodone. Ketoprofen tended to be somewhat slower in onset; peak pain relief was about the same and the duration of the effect tended to be 1 to 2 hours longer, particularly with the higher doses of ketoprofen.
# How Supplied
Ketoprofen capsules are available as follows:
- 50 mg: Blue cap and light blue body, imprinted “93” over "3193" on the cap and on the body, in bottles of 100.
- 75 mg: Blue cap and white body, imprinted “TEVA” on the cap and “3195” on the body, in bottles of 100 and 500.
## Storage
- Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ketoprofen Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Ketoprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orudis
- Orudis KT
- Oruvail
# Look-Alike Drug Names
There is limited information regarding Ketoprofen Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Actron | |
642c2ac06d6fb38ad5deba86e77d292ece4dcc90 | wikidoc | Herpangina | Herpangina
Synonyms: Vesicular stomatitis, Acute lymphonodular pharyngitis
# Overview
Herpangina is a self-limited infection of the upper respiratory tract caused by enteroviruses. Serotypes of coxsackie A virus are frequently implicated. Outbreaks of herpangina often occur during the summer period, and the pediatric age group is predominantly affected. Herpangina often begins with a sudden fever, sore throat, dysphagia, and the appearance of the enanthem. The diagnosis is usually clinical and it generally resolves within one week of infection without any sequelae.
# Historical Perspective
The name 'herpangina' was coined by Zahorsky, and he was also the first person to give a full description of the clinical entitity in 1920. The first isolation and description of the coxsackie virus was in 1948 by Dalldorf and Sickles.
# Causes
Herpangina is caused by enteroviruses. The majority of herpangina cases are caused by coxsackie A viruses (commonly A1, A2, A6, A8, A10, A16, and A22) but it can also be caused by other enteroviruses such as some serotypes of coxsackie B virus, echovirus and enterovirus 71.
# Pathophysiology
The mode of transmission of enteroviruses is usually via fecal–oral transmission. However, enteroviruses can also be spread through contact with virus-contaminated oral secretions, vesicular fluid, contaminated surfaces or fomites, and viral respiratory droplets. Following ingestion of the enterovirus, viral replication occurs in the lymphoid tissues of the oropharyngeal cavity and the small bowel (Peyer's patches). Dissemination of enteroviruses to the reticuloendothelial system and other parts of the body such as the skin and mucous membranes can occur, and this coincides with the onset of the clinical features.
# Risk Factors
Some of the risk factors that have been found to be associated with herpangina are:
- Attendance at a kindergarten/child care center
- Contact with herpangina cases
- Residence in rural areas
- Overcrowding
- Poor hygiene
- Low socioeconomic status
# Differential Diagnosis
The following diseases may mimic herpangina:
- Herpetic gingivostomatitis- This is caused by herpes simplex virus(HSV) infection, and affects the anterior oral cavity. It commonly affects the inner parts of the lips, the buccal mucosa, and the tongue. Gingivitis and cervical lymphadenitis can be seen in HSV infection but these are usually absent in herpangina.
- Bacterial pharyngitis
- Tonsillitis
- Aphthous stomatitis
- Hand-foot-mouth disease
Oral lesions caused by herpangina must be differentiated from other diseases presenting with pain and blistering within the mouth (gingivostomatitis and glossitis). The differentials include:
# Epidemiology
## Incidence
The incidence of herpangina has been found to have seasonal variations and there is usually a peak in the incidence during the summer season. The incidence was studied for a period of 8 years in Taiwan and was found to vary between 0.8-19.9 cases per sentinel physician per week.
## Age
Herpangina is seen predominantly in children and summer outbreaks are not uncommon. It occurs more frequently in children between the ages of 3-10yrs. Adolescents and young adults are occasionally affected.
## Sex
There is no known sex predilection.
# Natural History, Complications, Prognosis
## Natural History
Herpangina is a self-limited infection of the upper respiratory tract.
## Complications
Complications such as meningitis rarely occurs.
## Prognosis
The prognosis is excellent and complete resolution generally occurs in a week.
# Diagnosis
## History and Symptoms
The history and symptoms may include the following:
- Sudden fever
- Sore throat and dysphagia- These can occur several hours(up to 24 hours), before the appearance of the enanthem.
- Vomiting
- Abdominal pain
- Myalgia
- Headache
- Pharyngeal lesions
- Most patients do not appear severely ill
## Physical Examination
Examination of the throat can reveal the following:
- Erythema
- Exudate of the tonsils which is usually mild.
- Characteristic enanthem- Punctate macule which evolve over a period of 24 hours to 2-4mm erythematous papules which vesiculate, and then centrally ulcerate.
- The lesions are usually small in number, and evolve rapidly. The lesions are seen more commonly on the soft palate and uvula. The lesions can also be seen on the tonsils, posterior pharyngeal wall and the buccal mucosa.
## Laboratory Tests
- The diagnosis of herpangina is clinical.
- When unsure of the diagnosis, pharyngeal viral and bacterial cultures can be taken to exclude HSV infection and streptococcal pharyngitis.
- Approximately 1 week after infection, type-specific antibodies appear in the blood with maximum titer occurring in 3 weeks.
# Treatment
Herpangina is a self-limited infection, and the treatment comprises the management of the symptoms. This entails:
- Symptomatic treatment of sore throat with saline gargles, analgesic throat lozenges and liberal oral fluid intake.
- Analgesic medications for pain
- Antipyretic medications when indicated
- Avoidance of antiviral and antibacterial medications as symptoms generally resolve within 1 week.
# Prevention
The prevention of herpangina is best achieved by adoption of infection control practices such as:
- Good personal hygiene like hand-washing.
- Cleaning and disinfection of premises and objects/articles.
- Ensuring infected children are quarantined. | Herpangina
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Fatimo Biobaku M.B.B.S [2]
Synonyms: Vesicular stomatitis, Acute lymphonodular pharyngitis
# Overview
Herpangina is a self-limited infection of the upper respiratory tract caused by enteroviruses.[1] Serotypes of coxsackie A virus are frequently implicated. Outbreaks of herpangina often occur during the summer period, and the pediatric age group is predominantly affected.[2] Herpangina often begins with a sudden fever, sore throat, dysphagia, and the appearance of the enanthem. The diagnosis is usually clinical and it generally resolves within one week of infection without any sequelae.[1]
# Historical Perspective
The name 'herpangina' was coined by Zahorsky, and he was also the first person to give a full description of the clinical entitity in 1920.[3] The first isolation and description of the coxsackie virus was in 1948 by Dalldorf and Sickles.[3]
# Causes
Herpangina is caused by enteroviruses. The majority of herpangina cases are caused by coxsackie A viruses (commonly A1, A2, A6, A8, A10, A16, and A22) but it can also be caused by other enteroviruses such as some serotypes of coxsackie B virus, echovirus and enterovirus 71.[1][4][2]
# Pathophysiology
The mode of transmission of enteroviruses is usually via fecal–oral transmission.[5] However, enteroviruses can also be spread through contact with virus-contaminated oral secretions, vesicular fluid, contaminated surfaces or fomites, and viral respiratory droplets.[6][5] Following ingestion of the enterovirus, viral replication occurs in the lymphoid tissues of the oropharyngeal cavity and the small bowel (Peyer's patches).[5] Dissemination of enteroviruses to the reticuloendothelial system and other parts of the body such as the skin and mucous membranes can occur, and this coincides with the onset of the clinical features.[5]
# Risk Factors
Some of the risk factors that have been found to be associated with herpangina are:[7][8]
- Attendance at a kindergarten/child care center
- Contact with herpangina cases
- Residence in rural areas
- Overcrowding
- Poor hygiene
- Low socioeconomic status
# Differential Diagnosis
The following diseases may mimic herpangina:[1][2]
- Herpetic gingivostomatitis- This is caused by herpes simplex virus(HSV) infection, and affects the anterior oral cavity. It commonly affects the inner parts of the lips, the buccal mucosa, and the tongue. Gingivitis and cervical lymphadenitis can be seen in HSV infection but these are usually absent in herpangina.
- Bacterial pharyngitis
- Tonsillitis
- Aphthous stomatitis
- Hand-foot-mouth disease
Oral lesions caused by herpangina must be differentiated from other diseases presenting with pain and blistering within the mouth (gingivostomatitis and glossitis). The differentials include:
# Epidemiology
## Incidence
The incidence of herpangina has been found to have seasonal variations and there is usually a peak in the incidence during the summer season.[13] The incidence was studied for a period of 8 years in Taiwan and was found to vary between 0.8-19.9 cases per sentinel physician per week.[13]
## Age
Herpangina is seen predominantly in children and summer outbreaks are not uncommon.[2] It occurs more frequently in children between the ages of 3-10yrs.[1][2] Adolescents and young adults are occasionally affected.[2]
## Sex
There is no known sex predilection.[1]
# Natural History, Complications, Prognosis
## Natural History
Herpangina is a self-limited infection of the upper respiratory tract.[1]
## Complications
Complications such as meningitis rarely occurs.[8]
## Prognosis
The prognosis is excellent and complete resolution generally occurs in a week.[1]
# Diagnosis
## History and Symptoms
The history and symptoms may include the following:[2][1]
- Sudden fever
- Sore throat and dysphagia- These can occur several hours(up to 24 hours), before the appearance of the enanthem.
- Vomiting
- Abdominal pain
- Myalgia
- Headache
- Pharyngeal lesions
- Most patients do not appear severely ill
## Physical Examination
Examination of the throat can reveal the following:[2]
- Erythema
- Exudate of the tonsils which is usually mild.
- Characteristic enanthem- Punctate macule which evolve over a period of 24 hours to 2-4mm erythematous papules which vesiculate, and then centrally ulcerate.
- The lesions are usually small in number, and evolve rapidly. The lesions are seen more commonly on the soft palate and uvula. The lesions can also be seen on the tonsils, posterior pharyngeal wall and the buccal mucosa.
## Laboratory Tests[1]
- The diagnosis of herpangina is clinical.
- When unsure of the diagnosis, pharyngeal viral and bacterial cultures can be taken to exclude HSV infection and streptococcal pharyngitis.
- Approximately 1 week after infection, type-specific antibodies appear in the blood with maximum titer occurring in 3 weeks.
# Treatment
Herpangina is a self-limited infection, and the treatment comprises the management of the symptoms. This entails:[1]
- Symptomatic treatment of sore throat with saline gargles, analgesic throat lozenges and liberal oral fluid intake.
- Analgesic medications for pain
- Antipyretic medications when indicated
- Avoidance of antiviral and antibacterial medications as symptoms generally resolve within 1 week.
# Prevention
The prevention of herpangina is best achieved by adoption of infection control practices such as:[14]
- Good personal hygiene like hand-washing.
- Cleaning and disinfection of premises and objects/articles.
- Ensuring infected children are quarantined. | https://www.wikidoc.org/index.php/Acute_lymphonodular_pharyngitis | |
07139c752aaf547f910ed9b576c74e7d2cfa8ac9 | wikidoc | Long COVID | Long COVID
For COVID-19 main page, click here
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Synonyms and keywords: Long COVID Syndrome, long COVID, long-haul COVID, post-COVID-19 condition, post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), Long-hauler COVID-19, Long-tail COVID, Long-haulers, Post-acute COVID-19 syndrome, Acute post-COVID symptoms, Long post-COVID symptoms, Persistent post-COVID symptoms, Post-acute COVID-19, On-going symptomatic COVID-19, Chronic COVID-19
# Overview
Shortly after the COVID-19 pandemic onset, emerging studies showed that a considerable proportion of patients with COVID-19 might exhibit sustained postinfection sequelae. This condition has been defined by a variety of names, including long COVID or long-haul COVID, and post-COVID-19 condition. The absence of a universally standardized terminology has made characterization of the epidemiology, risk factors, clinical characteristics, and potential treatments options difficult. Symptoms may occur as an unpredictable combination of respiratory, cardiovascular, urological, neurological, and/or gastrointestinal manifestations. However, the most common symptoms include fatigue, dyspnea, and cognitive dysfunction (known as brain fog by the patients). Symptoms may begin following initial recovery from an acute COVID-19 episode or may persist from the initial acute episode. Symptoms might also fluctuate or relapse over time.
# Historical Perspective
- The term ‘Long COVID’ was first used as a Twitter hashtag by a patient who was not recovering from COVID-19. This patient-made term soon became a widely accepted concept by both the public and medical professionals.
- Currently, this condition is known by a variety of names, including long COVID, long-haul COVID, post-COVID-19 condition, post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS).
- This condition is listed in the ICD-10 classification as post-COVID-19 condition since September 2020.
# Definition
- On October 6, 2021, World Health Organization (WHO) released a clinical case definition of the post-COVID-19 condition through a robust, protocol-based methodology (Delphi consensus), which engaged a diverse group of representative patients, patient-researchers, external experts, WHO staff, and other stakeholders from multiple geographies. It was acknowledged that this definition may change with emerging new evidence and continuously evolving our understanding of the consequences of COVID-19.
- According to WHO clinical case definition, the post-COVID-19 condition is defined as:
Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
Common symptoms include fatigue, shortness of breath, cognitive dysfunction and generally have an impact on everyday functioning.
Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
Symptoms may also fluctuate or relapse over time.
A separate definition may be applicable for children.
Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
- Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
- Common symptoms include fatigue, shortness of breath, cognitive dysfunction and generally have an impact on everyday functioning.
Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
Symptoms may also fluctuate or relapse over time.
A separate definition may be applicable for children.
Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
- Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
- Symptoms may also fluctuate or relapse over time.
- A separate definition may be applicable for children.
- Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
- A summary of some published/available definitions of the post-COVID-19 condition include:
# Classification
There is no established system for the classification of long COVID.
# Pathophysiology
The exact pathogenesis of long COVID is not fully understood. A controlled study found no unique abnormalities
However, a number of putative pathophysiologic mechanisms have been suggested.
- 1) Long-term tissue damage:
Long-term tissue damage can result in the persistence of symptoms in different organs. For example:
Respiratory symptoms
Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough.
Neurologic symptoms
Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue.
Fatigue
Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include:
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
Cardiovascular symptoms
Autonomic symptoms and findings are common in an uncontrolled study
Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise.
- Long-term tissue damage can result in the persistence of symptoms in different organs. For example:
Respiratory symptoms
Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough.
Neurologic symptoms
Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue.
Fatigue
Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include:
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
Cardiovascular symptoms
Autonomic symptoms and findings are common in an uncontrolled study
Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise.
- Respiratory symptoms
Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough.
- Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough.
- Neurologic symptoms
Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue.
- Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue.
- Fatigue
Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include:
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
- Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include:
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
- Autonomic nervous system dysfunction
- Inflammation
- Channelopathies
- Inadequate cerebral perfusion
- Cardiovascular symptoms
Autonomic symptoms and findings are common in an uncontrolled study
Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise.
- Autonomic symptoms and findings are common in an uncontrolled study
- Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
- Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise.
- 2) Ongoing inflammation
Several studies have suggested the presence of an unresolved inflammation in patients recovering from COVID-19. This ongoing inflammation may result from a variety of reasons.
1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID.
2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain.
3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases.
4) Other mechanisms
In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- Several studies have suggested the presence of an unresolved inflammation in patients recovering from COVID-19. This ongoing inflammation may result from a variety of reasons.
1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID.
2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain.
3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases.
4) Other mechanisms
In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- 1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID.
- 2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain.
- 3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases.
- 4) Other mechanisms
In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- Reduced peak exercise aerobic capacity
- Impaired systemic oxygen extraction
- Abnormal ventilatory efficiency slope.
# Epidemiology and Demographics
- The reported incidence/prevalence of long COVID varies in different studies mainly due to the absence of single terminology and definition.
- A meta-analysis, including 47,910 patients (age 17-87 years), estimated that 80% of the patients with SARS-CoV-2 infections developed one or more long-term (ranging from 14 to 110 days) symptoms.
- Women seem to be more commonly affected by long COVID than men.
A cohort study found the COVID alpha variant found:
- "Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness."
- "In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint."
# Risk Factors
- There are no established risk factors for long COVID.
- However, according to several studies, the most common risk factors for the development of long COVID may include:
Older age
Female gender
Pre-existing comorbidities, such as obesity, asthma
More severity of the acute COVID-19 episode, including a prolonged hospitalization or ICU stay
However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
Medical complications during acute COVID-19 episode, such as secondary bacterial pneumonia, venous thromboembolism
Presence of a higher number of symptoms in the acute COVID-19 episode (i.e. an extended spectrum of symptoms) (more than five initial symptoms)
Increased levels of C-reactive protein and D-dimer
Decreased lymphocyte count
- Older age
- Female gender
- Pre-existing comorbidities, such as obesity, asthma
- More severity of the acute COVID-19 episode, including a prolonged hospitalization or ICU stay
However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
- However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
- Medical complications during acute COVID-19 episode, such as secondary bacterial pneumonia, venous thromboembolism
- Presence of a higher number of symptoms in the acute COVID-19 episode (i.e. an extended spectrum of symptoms) (more than five initial symptoms)
- Increased levels of C-reactive protein and D-dimer
- Decreased lymphocyte count
# Screening
There is insufficient evidence to recommend routine screening for long COVID.
# Natural History, Complications, and Prognosis
- The natural history, clinical course, long-term complications, and prognosis of long COVID-19 are still not completely understood.
- Manifestations of the post-COVID-19 condition vary considerably in terms of organ involvement and severity of symptoms; however, they generally impact the everyday functioning of affected patients.
- Symptoms might newly develop following initial recovery from an acute COVID-19 illness or occur as a persist from the initial episode.
- Symptoms might also fluctuate or relapse over time.
# Diagnosis
## Diagnostic Study of Choice
- According to a clinical case definition by WHO, the post-COVID-19 condition is defined as follow:
The post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
- The post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
## History and Symptoms
Long COVID can involve almost every organ.
The most common symptoms of long COVID include:
- Physical symptoms:
Fatigue
Dyspnea
Cough
Chest discomfort
Anosmia
- Fatigue
- Dyspnea
- Cough
- Chest discomfort
- Anosmia
- Neurocognitive symptoms:
Memory impairment and Cognitive dysfunction: described by patients as “brain fog”
Headache
- Memory impairment and Cognitive dysfunction: described by patients as “brain fog”
- Headache
- Psychologic symptoms:
Anxiety
Depression
Post-traumatic stress disorder (PTSD)
- Anxiety
- Depression
- Post-traumatic stress disorder (PTSD)
- Other less common symptoms include:
Sweating
Myalgias
Diarrhea
Hair Loss (Alopecia)
Joint Pain
Sicca Syndrome
Rhinitis
Dysgeusia
Poor Appetite
Dizziness
Vertigo
Insomnia
- Sweating
- Myalgias
- Diarrhea
- Hair Loss (Alopecia)
- Joint Pain
- Sicca Syndrome
- Rhinitis
- Dysgeusia
- Poor Appetite
- Dizziness
- Vertigo
- Insomnia
## Physical Examination
- In patients with cardiopulmonary symptoms, a throughout chest examination may provide a clue to the underlying condition:
On pulmonary examination:
Coarse crackles: a sign of fibrosis
Dullness on percussion: a sign of pleural effusion or consolidation
Egophony: A sign of consolidation
Fine basilar crackles: A sign of pulmonary edema
On cardiac examination, the following findings may provide a clue to the underlying cardiac complication:
Jugular venous distension
Peripheral edema
Orthostasis
Murmurs
Pericardial rub
Third or fourth heart sounds
- On pulmonary examination:
Coarse crackles: a sign of fibrosis
Dullness on percussion: a sign of pleural effusion or consolidation
Egophony: A sign of consolidation
Fine basilar crackles: A sign of pulmonary edema
- Coarse crackles: a sign of fibrosis
- Dullness on percussion: a sign of pleural effusion or consolidation
- Egophony: A sign of consolidation
- Fine basilar crackles: A sign of pulmonary edema
- On cardiac examination, the following findings may provide a clue to the underlying cardiac complication:
Jugular venous distension
Peripheral edema
- Jugular venous distension
- Peripheral edema
- Orthostasis
Murmurs
Pericardial rub
Third or fourth heart sounds
- Murmurs
- Pericardial rub
- Third or fourth heart sounds
## Laboratory Findings
There are no diagnostic laboratory findings associated with long COVID.
Symptoms do not correlate with the serology of SARS-CoV-2.
## Electrocardiography
In patients with cardiopulmonary symptoms, an ECG may be needed.
## X-ray
A chest x-ray may be helpful in the diagnosis of pulmonary complications of COVID-19 such as lung damage (ie, ground glass opacities, consolidation, interlobular septal thickening) and pleural effusion.
## Echocardiography or Ultrasound
In selected patients with cardiopulmonary symptoms, echocardiography may be necessary.
## CT scan
In patients with cardiopulmonary symptoms, a chest CT scan may be needed.
## MRI
There are no MRI findings associated with long COVID. However, a cardiac MRI may be helpful in the diagnosis of myocarditis in COVID-19 patients.
## Other Imaging Findings
There are no other imaging findings associated with long COVID.
## Other Diagnostic Studies
In selected patients with cardiopulmonary symptoms, Holter monitoring, cardiopulmonary exercise testing (CPET), and pulmonary function tests may be necessary.
# Treatment
Due to the diversity of symptoms and their severity, the mainstay of long COVID treatment is multidisciplinary and supportive. The management should focus on supporting self-management and individualized rehabilitation.
## Medical Therapy
- Dyspnea
Dyspnea in long COVID patients should be treated similar to non-COVID-19 patients. General measures in the management of dyspnea in long COVID patients may include:
Oxygen therapy
Breathing exercises:
Pursed lip breathing exercises
Deep breathing exercises
Pulmonary rehabilitation
In the presence of any identified underlying cardiac or pulmonary disease, referral to a cardiologist or pulmonologist and appropriate pharmacotherapy may be required.
- Dyspnea in long COVID patients should be treated similar to non-COVID-19 patients. General measures in the management of dyspnea in long COVID patients may include:
Oxygen therapy
Breathing exercises:
Pursed lip breathing exercises
Deep breathing exercises
Pulmonary rehabilitation
- Oxygen therapy
- Breathing exercises:
Pursed lip breathing exercises
Deep breathing exercises
- Pursed lip breathing exercises
- Deep breathing exercises
- Pulmonary rehabilitation
- In the presence of any identified underlying cardiac or pulmonary disease, referral to a cardiologist or pulmonologist and appropriate pharmacotherapy may be required.
- Cough
Cough should be managed in a similar to cough in patients with post-viral cough syndrome.
Attention should be paid to diagnose and treat other exacerbating or contributing factors such as gastrointestinal reflux disease and asthma.
Over-the-counter cough suppressants, including benzonatate, guaifenesin, and dextromethorphan are the mainstay of treatment.
- Cough should be managed in a similar to cough in patients with post-viral cough syndrome.
- Attention should be paid to diagnose and treat other exacerbating or contributing factors such as gastrointestinal reflux disease and asthma.
- Over-the-counter cough suppressants, including benzonatate, guaifenesin, and dextromethorphan are the mainstay of treatment.
- Cardiac injury
Long COVID patients with evidence of cardiac injury should be referred to cardiology services.
Patients recovering from cardiac injury with impaired functional status (eg, New York Heart Association class II or higher) should undergo cardiac rehabilitation if no contraindications are present.
- Long COVID patients with evidence of cardiac injury should be referred to cardiology services.
- Patients recovering from cardiac injury with impaired functional status (eg, New York Heart Association class II or higher) should undergo cardiac rehabilitation if no contraindications are present.
- Orthostasis
Orthostasis and dysautonomia, such as unexplained sinus tachycardia, dizziness on standing, is initially managed conservatively with compression stockings, abdominal binder, increased intake of fluid and salts, physical therapy/rehabilitation, and behavioral modifications.
In patients with postural orthostatic tachycardia syndrome (PoTS) and inadequate response to non-pharmacological therapy, beta-blockers, ivabradine, or fludrocortisone (with blood pressure and response monitoring) might be considered.
- Orthostasis and dysautonomia, such as unexplained sinus tachycardia, dizziness on standing, is initially managed conservatively with compression stockings, abdominal binder, increased intake of fluid and salts, physical therapy/rehabilitation, and behavioral modifications.
- In patients with postural orthostatic tachycardia syndrome (PoTS) and inadequate response to non-pharmacological therapy, beta-blockers, ivabradine, or fludrocortisone (with blood pressure and response monitoring) might be considered.
- Olfactory/gustatory symptoms
In most patients with a loss or decrease in sense of smell or taste, symptoms improve slowly over several weeks and do not require medical intervention. Patients may need education on food and home safety.
In patients with persistent symptoms, olfactory training may be appropriate. If conservative management fails, referral to an otolaryngologist and specialized taste and smell clinic may also be considered.
- In most patients with a loss or decrease in sense of smell or taste, symptoms improve slowly over several weeks and do not require medical intervention. Patients may need education on food and home safety.
- In patients with persistent symptoms, olfactory training may be appropriate. If conservative management fails, referral to an otolaryngologist and specialized taste and smell clinic may also be considered.
- Fatigue
A Consensus Guidance Statement provides practical guidance to clinicians in the treatment of fatigue in postacute sequelae of SARS‐CoV‐2 infection (PASC) patients.
Conservative management
1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
2) Educating patients on energy conservation strategies
3) Encouraging a healthy diet and adequate hydration
4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
Pharmacologic therapy and supplements
A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
These include:
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- A Consensus Guidance Statement provides practical guidance to clinicians in the treatment of fatigue in postacute sequelae of SARS‐CoV‐2 infection (PASC) patients.
Conservative management
1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
2) Educating patients on energy conservation strategies
3) Encouraging a healthy diet and adequate hydration
4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
Pharmacologic therapy and supplements
A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
These include:
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- Conservative management
1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
2) Educating patients on energy conservation strategies
3) Encouraging a healthy diet and adequate hydration
4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
- 1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
- The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
- The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
- Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
- 2) Educating patients on energy conservation strategies
- 3) Encouraging a healthy diet and adequate hydration
- 4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
- Pharmacologic therapy and supplements
A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
These include:
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
- These include:
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
- Branched‐chain amino acids
- Omega 3 fatty acids
- Vitamin B12
- Vitamin C
- Vitamin D
- Magnesium
- L‐carnitine
- Coenzyme Q10
- Ginseng
- Echinacea
- Amantadine
- Modafinil
- Methylphenidate
- Antivirals/antibiotics/antiparasitics
- Antidepressants
- Cytokine inhibitors
- Galantamine
- Glucocorticoids
- Immunoglobulins
- Rituximab
- However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
- Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- Weight loss
In patients with long COVID, weight loss is multifactorial and may occur due to a combination of malnutrition, loss of appetite, catabolic state, swallowing difficulty, and alterations in taste and smell.
Patients should be encouraged to eat small, frequent meals with protein and calorie supplementation. Nutrition consultation and referral to a dietician may be required in selected patients with severe weight loss.
- In patients with long COVID, weight loss is multifactorial and may occur due to a combination of malnutrition, loss of appetite, catabolic state, swallowing difficulty, and alterations in taste and smell.
- Patients should be encouraged to eat small, frequent meals with protein and calorie supplementation. Nutrition consultation and referral to a dietician may be required in selected patients with severe weight loss.
- Psychological and emotional issues
In patients experiencing emotional distress, mood disturbances, anxiety, or symptoms of post-traumatic stress disorder, mental health assessment and possible referral to a psychiatrist may be required.
Cognitive behavioral therapy may benefit patients with anxiety, depression and stress.
Neurocognitive concerns may benefit from hyperbaric oxygen
- In patients experiencing emotional distress, mood disturbances, anxiety, or symptoms of post-traumatic stress disorder, mental health assessment and possible referral to a psychiatrist may be required.
- Cognitive behavioral therapy may benefit patients with anxiety, depression and stress.
- Neurocognitive concerns may benefit from hyperbaric oxygen
- Alopecia
There is no specific therapy for alopecia in COVID-19 patients, and it should be managed similarly to non-COVID-19 patients.
In patients with concomitant malnutrition, nutritional deficiencies should be corrected.
- There is no specific therapy for alopecia in COVID-19 patients, and it should be managed similarly to non-COVID-19 patients.
- In patients with concomitant malnutrition, nutritional deficiencies should be corrected.
- Insomnia
All patients with insomnia should be educated on sleep hygiene guidelines, stimulus control instructions, and relaxation techniques. Short-term pharmacologic treatment with benzodiazepines or non-benzodiazepine hypnotics may be needed in selected patients.
- All patients with insomnia should be educated on sleep hygiene guidelines, stimulus control instructions, and relaxation techniques. Short-term pharmacologic treatment with benzodiazepines or non-benzodiazepine hypnotics may be needed in selected patients.
## Primary Prevention
The most effective measure to prevent the post-COVID-19 condition is to prevent COVID-19. These primary prevention strategies include:
- Vaccination
- Masking
- Social distancing
- Hand hygiene
## Secondary Prevention
There are no established measures for the secondary prevention of long COVID. | Long COVID
For COVID-19 main page, click here
For COVID-19 frequently asked inpatient questions, click here
For COVID-19 frequently asked outpatient questions, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]
Synonyms and keywords: Long COVID Syndrome, long COVID, long-haul COVID, post-COVID-19 condition, post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), chronic COVID syndrome (CCS), Long-hauler COVID-19, Long-tail COVID, Long-haulers, Post-acute COVID-19 syndrome, Acute post-COVID symptoms, Long post-COVID symptoms, Persistent post-COVID symptoms, Post-acute COVID-19, On-going symptomatic COVID-19, Chronic COVID-19
# Overview
Shortly after the COVID-19 pandemic onset, emerging studies showed that a considerable proportion of patients with COVID-19 might exhibit sustained postinfection sequelae. This condition has been defined by a variety of names, including long COVID or long-haul COVID, and post-COVID-19 condition. The absence of a universally standardized terminology has made characterization of the epidemiology, risk factors, clinical characteristics, and potential treatments options difficult. Symptoms may occur as an unpredictable combination of respiratory, cardiovascular, urological, neurological, and/or gastrointestinal manifestations. However, the most common symptoms include fatigue, dyspnea, and cognitive dysfunction (known as brain fog by the patients). Symptoms may begin following initial recovery from an acute COVID-19 episode or may persist from the initial acute episode. Symptoms might also fluctuate or relapse over time.
# Historical Perspective
- The term ‘Long COVID’ was first used as a Twitter hashtag by a patient who was not recovering from COVID-19. [1] This patient-made term soon became a widely accepted concept by both the public and medical professionals.
- Currently, this condition is known by a variety of names, including long COVID, long-haul COVID, post-COVID-19 condition, post-COVID-19 syndrome, post-acute sequelae of COVID-19 (PASC), or chronic COVID syndrome (CCS).
- This condition is listed in the ICD-10 classification as post-COVID-19 condition since September 2020. [2]
# Definition
- On October 6, 2021, World Health Organization (WHO) released a clinical case definition of the post-COVID-19 condition through a robust, protocol-based methodology (Delphi consensus), which engaged a diverse group of representative patients, patient-researchers, external experts, WHO staff, and other stakeholders from multiple geographies. [3] It was acknowledged that this definition may change with emerging new evidence and continuously evolving our understanding of the consequences of COVID-19.
- According to WHO clinical case definition, the post-COVID-19 condition is defined as: [3]
Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
Common symptoms include fatigue, shortness of breath, cognitive dysfunction and generally have an impact on everyday functioning.
Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
Symptoms may also fluctuate or relapse over time.
A separate definition may be applicable for children.
Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
- Post COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
- Common symptoms include fatigue, shortness of breath, cognitive dysfunction and generally have an impact on everyday functioning.
Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
Symptoms may also fluctuate or relapse over time.
A separate definition may be applicable for children.
Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
- Symptoms may be new-onset following initial recovery from an acute COVID-19 episode or persist from the initial illness.
- Symptoms may also fluctuate or relapse over time.
- A separate definition may be applicable for children.
- Notes: There is no minimum number of symptoms required for the diagnosis; though symptoms involving different organs systems and clusters have been described.
- A summary of some published/available definitions of the post-COVID-19 condition include:
# Classification
There is no established system for the classification of long COVID.
# Pathophysiology
The exact pathogenesis of long COVID is not fully understood. A controlled study found no unique abnormalities[11]
However, a number of putative pathophysiologic mechanisms have been suggested.
- 1) Long-term tissue damage:
Long-term tissue damage can result in the persistence of symptoms in different organs. For example:
Respiratory symptoms
Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough. [12] [13] [14] [15] [16] [17]
Neurologic symptoms
Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue. [18]
Fatigue
Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include: [19] [20] [21] [18]
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
Cardiovascular symptoms
Autonomic symptoms and findings are common in an uncontrolled study[22]
Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise. [23] [20] [24]
- Long-term tissue damage can result in the persistence of symptoms in different organs. For example:
Respiratory symptoms
Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough. [12] [13] [14] [15] [16] [17]
Neurologic symptoms
Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue. [18]
Fatigue
Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include: [19] [20] [21] [18]
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
Cardiovascular symptoms
Autonomic symptoms and findings are common in an uncontrolled study[22]
Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise. [23] [20] [24]
- Respiratory symptoms
Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough. [12] [13] [14] [15] [16] [17]
- Lung fibrosis may be the cause of respiratory symptoms, such as dyspnea and cough. [12] [13] [14] [15] [16] [17]
- Neurologic symptoms
Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue. [18]
- Structural and metabolic abnormalities in the brain and brainstem may be the cause of neurologic symptoms such as headache, delirium, memory loss, anosmia, and fatigue. [18]
- Fatigue
Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include: [19] [20] [21] [18]
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
- Chronic fatigue occurs as a complex syndrome and a few mechanisms have been suggested. These include: [19] [20] [21] [18]
Autonomic nervous system dysfunction
Inflammation
Channelopathies
Inadequate cerebral perfusion
- Autonomic nervous system dysfunction
- Inflammation
- Channelopathies
- Inadequate cerebral perfusion
- Cardiovascular symptoms
Autonomic symptoms and findings are common in an uncontrolled study[22]
Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise. [23] [20] [24]
- Autonomic symptoms and findings are common in an uncontrolled study[22]
- Cardiac injury occurs in a substantial proportion of patients during acute COVID-19 episodes. Resulting cardiac abnormalities (such as impaired contractile function and cardiac remodeling) and myocardial inflammation may account for symptoms such as chest pain, palpitations, and tachycardia.
- Cardiovascular and respiratory symptoms might also be due to damages of the intrathoracic chemo and mecano-receptors, which are involved in the control and regulation of respiration and heart rate. The SARS-CoV-2 neurotropism (i.e., cell invasion and damage), microcirculation or autoimmune disorders have been suggested as the possible mechanisms for such damages. This hypothesis seems to explain many dysautonomic symptoms which occur due to a dysregulated rate in respiration or heart rate. These symptoms include breathlessness, exercise intolerance, palpitations, or orthostatic malaise. [23] [20] [24]
- 2) Ongoing inflammation
Several studies have suggested the presence of an unresolved inflammation in patients recovering from COVID-19. This ongoing inflammation may result from a variety of reasons.
1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. [25] [26] [27] [28] This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID. [29] [30]
2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain. [31]
3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases. [32]
4) Other mechanisms
In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. [33] The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- Several studies have suggested the presence of an unresolved inflammation in patients recovering from COVID-19. This ongoing inflammation may result from a variety of reasons.
1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. [25] [26] [27] [28] This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID. [29] [30]
2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain. [31]
3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases. [32]
4) Other mechanisms
In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. [33] The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- 1) Viral persistence in the gastrointestinal tract: Studies have shown the persistence of the virus in the gastrointestinal tract (in the gastric and intestinal cells) after recovering from acute COVID-19 episodes due to the high expression of ACE2 receptors in these cells. Increased fecal shedding of the SARS-CoV-2 virus has been shown in some studies. [25] [26] [27] [28] This may trigger a state of immune activation and ongoing inflammation in the body and also may explain the relatively high prevalence (up to 30%) of gastrointestinal manifestations (e.g. appetite loss, nausea, vomiting, diarrhea, and abdominal discomfort) in patients with long COVID. [29] [30]
- 2) Lymphopenia: Increased levels of pro-inflammatory markers (e.g. CRP, IL-6, and D-dimer) and lymphopenia occur during acute COVID-19 episodes and have been shown to be associated with long COVID symptoms, particularly myalgia, fatigue, and joint pain. [31]
- 3) Autoimmunity: Recently, T-cells and B-cells dysfunction have been suggested to promote long COVID pathophysiology similar to autoimmune diseases. [32]
- 4) Other mechanisms
In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. [33] The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- In a recent study using Invasive Cardiopulmonary Exercise Testing (iCPET), the pathophysiologic mechanism of exercise intolerance in post-COVID-19 long-haul syndrome has been investigated. [33] The results of the study showed that patients without cardiopulmonary disease who have recovered from COVID-19 had a marked decrease in peak oxygen consumption and an exaggerated hyperventilation response during exercise. This means that patients who have recovered from COVID-19 had:
Reduced peak exercise aerobic capacity
Impaired systemic oxygen extraction
Abnormal ventilatory efficiency slope.
- Reduced peak exercise aerobic capacity
- Impaired systemic oxygen extraction
- Abnormal ventilatory efficiency slope.
# Epidemiology and Demographics
- The reported incidence/prevalence of long COVID varies in different studies mainly due to the absence of single terminology and definition.
- A meta-analysis, including 47,910 patients (age 17-87 years), estimated that 80% of the patients with SARS-CoV-2 infections developed one or more long-term (ranging from 14 to 110 days) symptoms. [34]
- Women seem to be more commonly affected by long COVID than men. [35]
A cohort study found the COVID alpha variant found[36]:
- "Persistent symptoms in COVID-19-positive participants at 90-150 days after COVID-19 compared with before COVID-19 and compared with matched controls included chest pain, difficulties with breathing, pain when breathing, painful muscles, ageusia or anosmia, tingling extremities, lump in throat, feeling hot and cold alternately, heavy arms or legs, and general tiredness."
- "In 12·7% of patients, these symptoms could be attributed to COVID-19, as 381 (21·4%) of 1782 COVID-19-positive participants versus 361 (8·7%) of 4130 COVID-19-negative controls had at least one of these core symptoms substantially increased to at least moderate severity at 90-150 days after COVID-19 diagnosis or matched timepoint."
# Risk Factors
- There are no established risk factors for long COVID.
- However, according to several studies, the most common risk factors for the development of long COVID may include: [34] [35] [37]
Older age
Female gender
Pre-existing comorbidities, such as obesity, asthma
More severity of the acute COVID-19 episode, including a prolonged hospitalization or ICU stay
However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
Medical complications during acute COVID-19 episode, such as secondary bacterial pneumonia, venous thromboembolism
Presence of a higher number of symptoms in the acute COVID-19 episode (i.e. an extended spectrum of symptoms) (more than five initial symptoms)
Increased levels of C-reactive protein and D-dimer
Decreased lymphocyte count
- Older age
- Female gender
- Pre-existing comorbidities, such as obesity, asthma
- More severity of the acute COVID-19 episode, including a prolonged hospitalization or ICU stay
However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
- However, emerging data suggest that even patients with a less severe initial episode of COVID-19, who had not required hospitalization, may also experience persistent symptoms of post-COVID-19 condition
- Medical complications during acute COVID-19 episode, such as secondary bacterial pneumonia, venous thromboembolism
- Presence of a higher number of symptoms in the acute COVID-19 episode (i.e. an extended spectrum of symptoms) (more than five initial symptoms)
- Increased levels of C-reactive protein and D-dimer
- Decreased lymphocyte count
# Screening
There is insufficient evidence to recommend routine screening for long COVID.
# Natural History, Complications, and Prognosis
- The natural history, clinical course, long-term complications, and prognosis of long COVID-19 are still not completely understood.
- Manifestations of the post-COVID-19 condition vary considerably in terms of organ involvement and severity of symptoms; however, they generally impact the everyday functioning of affected patients. [3]
- Symptoms might newly develop following initial recovery from an acute COVID-19 illness or occur as a persist from the initial episode. [3]
- Symptoms might also fluctuate or relapse over time. [3]
# Diagnosis
## Diagnostic Study of Choice
- According to a clinical case definition by WHO, the post-COVID-19 condition is defined as follow: [3]
The post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
- The post-COVID-19 condition occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset, with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.
## History and Symptoms
Long COVID can involve almost every organ.
The most common symptoms of long COVID include: [3] [34] [38] [39]
- Physical symptoms:
Fatigue
Dyspnea
Cough
Chest discomfort
Anosmia
- Fatigue
- Dyspnea
- Cough
- Chest discomfort
- Anosmia
- Neurocognitive symptoms:
Memory impairment and Cognitive dysfunction: described by patients as “brain fog”
Headache
- Memory impairment and Cognitive dysfunction: described by patients as “brain fog”
- Headache
- Psychologic symptoms:
Anxiety
Depression
Post-traumatic stress disorder (PTSD)
- Anxiety
- Depression
- Post-traumatic stress disorder (PTSD)
- Other less common symptoms include:
Sweating
Myalgias
Diarrhea
Hair Loss (Alopecia)
Joint Pain
Sicca Syndrome
Rhinitis
Dysgeusia
Poor Appetite
Dizziness
Vertigo
Insomnia
- Sweating
- Myalgias
- Diarrhea
- Hair Loss (Alopecia)
- Joint Pain
- Sicca Syndrome
- Rhinitis
- Dysgeusia
- Poor Appetite
- Dizziness
- Vertigo
- Insomnia
## Physical Examination
- In patients with cardiopulmonary symptoms, a throughout chest examination may provide a clue to the underlying condition:
On pulmonary examination:
Coarse crackles: a sign of fibrosis
Dullness on percussion: a sign of pleural effusion or consolidation
Egophony: A sign of consolidation
Fine basilar crackles: A sign of pulmonary edema
On cardiac examination, the following findings may provide a clue to the underlying cardiac complication:
Jugular venous distension
Peripheral edema
Orthostasis
Murmurs
Pericardial rub
Third or fourth heart sounds
- On pulmonary examination:
Coarse crackles: a sign of fibrosis
Dullness on percussion: a sign of pleural effusion or consolidation
Egophony: A sign of consolidation
Fine basilar crackles: A sign of pulmonary edema
- Coarse crackles: a sign of fibrosis
- Dullness on percussion: a sign of pleural effusion or consolidation
- Egophony: A sign of consolidation
- Fine basilar crackles: A sign of pulmonary edema
- On cardiac examination, the following findings may provide a clue to the underlying cardiac complication:
Jugular venous distension
Peripheral edema
- Jugular venous distension
- Peripheral edema
- Orthostasis
Murmurs
Pericardial rub
Third or fourth heart sounds
- Murmurs
- Pericardial rub
- Third or fourth heart sounds
## Laboratory Findings
There are no diagnostic laboratory findings associated with long COVID.
Symptoms do not correlate with the serology of SARS-CoV-2.
## Electrocardiography
In patients with cardiopulmonary symptoms, an ECG may be needed.
## X-ray
A chest x-ray may be helpful in the diagnosis of pulmonary complications of COVID-19 such as lung damage (ie, ground glass opacities, consolidation, interlobular septal thickening) and pleural effusion.
## Echocardiography or Ultrasound
In selected patients with cardiopulmonary symptoms, echocardiography may be necessary.
## CT scan
In patients with cardiopulmonary symptoms, a chest CT scan may be needed.
## MRI
There are no MRI findings associated with long COVID. However, a cardiac MRI may be helpful in the diagnosis of myocarditis in COVID-19 patients.
## Other Imaging Findings
There are no other imaging findings associated with long COVID.
## Other Diagnostic Studies
In selected patients with cardiopulmonary symptoms, Holter monitoring, cardiopulmonary exercise testing (CPET), and pulmonary function tests may be necessary.
# Treatment
Due to the diversity of symptoms and their severity, the mainstay of long COVID treatment is multidisciplinary and supportive. The management should focus on supporting self-management and individualized rehabilitation. [40] [41]
## Medical Therapy
- Dyspnea
Dyspnea in long COVID patients should be treated similar to non-COVID-19 patients. General measures in the management of dyspnea in long COVID patients may include: [42]
Oxygen therapy
Breathing exercises:
Pursed lip breathing exercises
Deep breathing exercises
Pulmonary rehabilitation
In the presence of any identified underlying cardiac or pulmonary disease, referral to a cardiologist or pulmonologist and appropriate pharmacotherapy may be required.
- Dyspnea in long COVID patients should be treated similar to non-COVID-19 patients. General measures in the management of dyspnea in long COVID patients may include: [42]
Oxygen therapy
Breathing exercises:
Pursed lip breathing exercises
Deep breathing exercises
Pulmonary rehabilitation
- Oxygen therapy
- Breathing exercises:
Pursed lip breathing exercises
Deep breathing exercises
- Pursed lip breathing exercises
- Deep breathing exercises
- Pulmonary rehabilitation
- In the presence of any identified underlying cardiac or pulmonary disease, referral to a cardiologist or pulmonologist and appropriate pharmacotherapy may be required.
- Cough
Cough should be managed in a similar to cough in patients with post-viral cough syndrome.
Attention should be paid to diagnose and treat other exacerbating or contributing factors such as gastrointestinal reflux disease and asthma.
Over-the-counter cough suppressants, including benzonatate, guaifenesin, and dextromethorphan are the mainstay of treatment.
- Cough should be managed in a similar to cough in patients with post-viral cough syndrome.
- Attention should be paid to diagnose and treat other exacerbating or contributing factors such as gastrointestinal reflux disease and asthma.
- Over-the-counter cough suppressants, including benzonatate, guaifenesin, and dextromethorphan are the mainstay of treatment.
- Cardiac injury
Long COVID patients with evidence of cardiac injury should be referred to cardiology services.
Patients recovering from cardiac injury with impaired functional status (eg, New York Heart Association class II or higher) should undergo cardiac rehabilitation if no contraindications are present.
- Long COVID patients with evidence of cardiac injury should be referred to cardiology services.
- Patients recovering from cardiac injury with impaired functional status (eg, New York Heart Association class II or higher) should undergo cardiac rehabilitation if no contraindications are present.
- Orthostasis
Orthostasis and dysautonomia, such as unexplained sinus tachycardia, dizziness on standing, is initially managed conservatively with compression stockings, abdominal binder, increased intake of fluid and salts, physical therapy/rehabilitation, and behavioral modifications.
In patients with postural orthostatic tachycardia syndrome (PoTS) and inadequate response to non-pharmacological therapy, beta-blockers, ivabradine, or fludrocortisone (with blood pressure and response monitoring) might be considered.
- Orthostasis and dysautonomia, such as unexplained sinus tachycardia, dizziness on standing, is initially managed conservatively with compression stockings, abdominal binder, increased intake of fluid and salts, physical therapy/rehabilitation, and behavioral modifications.
- In patients with postural orthostatic tachycardia syndrome (PoTS) and inadequate response to non-pharmacological therapy, beta-blockers, ivabradine, or fludrocortisone (with blood pressure and response monitoring) might be considered.
- Olfactory/gustatory symptoms
In most patients with a loss or decrease in sense of smell or taste, symptoms improve slowly over several weeks and do not require medical intervention. Patients may need education on food and home safety.
In patients with persistent symptoms, olfactory training may be appropriate. If conservative management fails, referral to an otolaryngologist and specialized taste and smell clinic may also be considered.
- In most patients with a loss or decrease in sense of smell or taste, symptoms improve slowly over several weeks and do not require medical intervention. Patients may need education on food and home safety.
- In patients with persistent symptoms, olfactory training may be appropriate. If conservative management fails, referral to an otolaryngologist and specialized taste and smell clinic may also be considered.
- Fatigue
A Consensus Guidance Statement provides practical guidance to clinicians in the treatment of fatigue in postacute sequelae of SARS‐CoV‐2 infection (PASC) patients.
Conservative management
1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
2) Educating patients on energy conservation strategies
3) Encouraging a healthy diet and adequate hydration
4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
Pharmacologic therapy and supplements
A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
These include: [43] [44] [45] [46] [46]
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- A Consensus Guidance Statement provides practical guidance to clinicians in the treatment of fatigue in postacute sequelae of SARS‐CoV‐2 infection (PASC) patients.
Conservative management
1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
2) Educating patients on energy conservation strategies
3) Encouraging a healthy diet and adequate hydration
4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
Pharmacologic therapy and supplements
A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
These include: [43] [44] [45] [46] [46]
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- Conservative management
1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
2) Educating patients on energy conservation strategies
3) Encouraging a healthy diet and adequate hydration
4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
- 1) Initiation of an individualized and structured, titrated return to activity program (individualized rehabilitation)
The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
- The goal of such a rehabilitation program should be restoring patients to their previous levels of activity and improve quality of life
- The titration approach ensures that patients are engaged in activities at a submaximal level to avoid exacerbation of fatigue.
- Level of activity should be adjusted according to change in fatigue-related symptoms that develop during or after activity.
- 2) Educating patients on energy conservation strategies
- 3) Encouraging a healthy diet and adequate hydration
- 4) Treatment of any underlying medical conditions such as pain, insomnia/sleep disorders (including poor sleep hygiene), and mood problems that may be contributing and/or aggravating fatigue.
- Pharmacologic therapy and supplements
A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
These include: [43] [44] [45] [46] [46]
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- A number of herbal remedies/supplements and pharmacologic agents have been used in the treatment of chronic fatigue in other causes of chronic illness (eg, multiple sclerosis, fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), cancer, brain injury, and Parkinson's disease).
- These include: [43] [44] [45] [46] [46]
Branched‐chain amino acids
Omega 3 fatty acids
Vitamin B12
Vitamin C
Vitamin D
Magnesium
L‐carnitine
Coenzyme Q10
Ginseng
Echinacea
Amantadine
Modafinil
Methylphenidate
Antivirals/antibiotics/antiparasitics
Antidepressants
Cytokine inhibitors
Galantamine
Glucocorticoids
Immunoglobulins
Rituximab
- Branched‐chain amino acids
- Omega 3 fatty acids
- Vitamin B12
- Vitamin C
- Vitamin D
- Magnesium
- L‐carnitine
- Coenzyme Q10
- Ginseng
- Echinacea
- Amantadine
- Modafinil
- Methylphenidate
- Antivirals/antibiotics/antiparasitics
- Antidepressants
- Cytokine inhibitors
- Galantamine
- Glucocorticoids
- Immunoglobulins
- Rituximab
- However, it should be noted that due to limited scientific evidence, currently there is no general consensus on routine administration of these supplements/medications. Thus, they may be considered on a case‐by‐case basis.
- Other therapeutic interventions such as acupuncture have been suggested in the treatment of fatigue.
- Weight loss
In patients with long COVID, weight loss is multifactorial and may occur due to a combination of malnutrition, loss of appetite, catabolic state, swallowing difficulty, and alterations in taste and smell.
Patients should be encouraged to eat small, frequent meals with protein and calorie supplementation. Nutrition consultation and referral to a dietician may be required in selected patients with severe weight loss.
- In patients with long COVID, weight loss is multifactorial and may occur due to a combination of malnutrition, loss of appetite, catabolic state, swallowing difficulty, and alterations in taste and smell.
- Patients should be encouraged to eat small, frequent meals with protein and calorie supplementation. Nutrition consultation and referral to a dietician may be required in selected patients with severe weight loss.
- Psychological and emotional issues
In patients experiencing emotional distress, mood disturbances, anxiety, or symptoms of post-traumatic stress disorder, mental health assessment and possible referral to a psychiatrist may be required.
Cognitive behavioral therapy may benefit patients with anxiety, depression and stress.
Neurocognitive concerns may benefit from hyperbaric oxygen[47]
- In patients experiencing emotional distress, mood disturbances, anxiety, or symptoms of post-traumatic stress disorder, mental health assessment and possible referral to a psychiatrist may be required.
- Cognitive behavioral therapy may benefit patients with anxiety, depression and stress.
- Neurocognitive concerns may benefit from hyperbaric oxygen[47]
- Alopecia
There is no specific therapy for alopecia in COVID-19 patients, and it should be managed similarly to non-COVID-19 patients.
In patients with concomitant malnutrition, nutritional deficiencies should be corrected.
- There is no specific therapy for alopecia in COVID-19 patients, and it should be managed similarly to non-COVID-19 patients.
- In patients with concomitant malnutrition, nutritional deficiencies should be corrected.
- Insomnia
All patients with insomnia should be educated on sleep hygiene guidelines, stimulus control instructions, and relaxation techniques. Short-term pharmacologic treatment with benzodiazepines or non-benzodiazepine hypnotics may be needed in selected patients.
- All patients with insomnia should be educated on sleep hygiene guidelines, stimulus control instructions, and relaxation techniques. Short-term pharmacologic treatment with benzodiazepines or non-benzodiazepine hypnotics may be needed in selected patients.
## Primary Prevention
The most effective measure to prevent the post-COVID-19 condition is to prevent COVID-19. These primary prevention strategies include:
- Vaccination[48]
- Masking
- Social distancing
- Hand hygiene
## Secondary Prevention
There are no established measures for the secondary prevention of long COVID. | https://www.wikidoc.org/index.php/Acute_post-COVID-19_symptoms | |
f6ac4a515d02bcdb77164a2c506c24b29391bcc4 | wikidoc | Neuropathy | Neuropathy
# Overview
Neuropathic pain results from damage or disease affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, and pain produced by normally non-painful stimuli (allodynia). Neuropathic pain may have continuous and/or episodic (paroxysmal) components. The latter are likened to an electric shock. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching. Nociceptive pain, by contrast, is more commonly described as aching.
Up to 7% to 8% of the European population is affected and in 5% of persons it may be severe.
Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
# Cause
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes (see diabetic neuropathy) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery.
## Drug Causes
- Bicalutamide
- Crizotinib
- Cytarabine
- Docetaxel
- Doxorubicin Hydrochloride
- Efavirenz
- Isoniazid
- Leuprolide
- Megestrol
- Oxaliplatin
- Pergolide
- Procarbazine
- Sorafenib
- Teniposide
- Valdecoxib
# Mechanisms
THe proportion of loss of affects clinical symptoms.
## Peripheral
After a peripheral nerve lesion, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and heightened sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called "peripheral sensitization".
## Central
The (spinal cord) dorsal horn neurons give rise to the spinothalamic tract (STT), which constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization is an important mechanism of persistent neuropathic pain.
Other mechanisms, however, may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity.”
Neuroglia ("glial cells") may play a role in central sensitization. Peripheral nerve injury induces glia to release proinflammatory cytokines and glutamate which, in turn influence neurons.
## Mechanisms at light-microscopic and submicroscopic levels
The phenomenon described above are dependent on changes at light-microscopic and submicroscopic levels. Altered expression of ion channels, changes in neurotransmitters and their receptors as well as altered gene expression in response to neural input are at play.
# Treatments
Neuropathic pain can be very difficult to treat with only some 40-60% of patients achieving partial relief.
In addition to the work of Dworkin, O'Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy. These have combined evidence from randomized controlled trials with expert opinion.
Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.
It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as "antidepressants" and "anti-epileptic drugs" (AED's). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.
Favored treatments are certain antidepressants e.g. tricyclics and selective serotonin-norepinephrine reuptake inhibitors (SNRI's), anticonvulsants, especially pregabalin (Lyrica) and gabapentin (Neurontin), and topical lidocaine. Opioid analgesics and tramadol are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive receptors, or desensitize C fibers such that they transmit fewer signals.
Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the brainstem.
## Antidepressants
The functioning of antidepressants is different in neuropathic pain from that observed in depression. Activation of descending norepinephrinergic and serotonergic pathways to the spinal cord limit pain signals ascending to the brain. Antidepressants will relieve neuropathic pain in non-depressed persons.
In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.
Similarly, compounds that only block norepinephrine reuptake also do not improve neuropathic pain. Dual serotonin-norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and milnacipran, as well as tricyclic antidepressants such as amitriptyline, nortriptyline, and desipramine improve neuropathic pain and are considered first-line medications for this condition.
Bupropion has been found to have efficacy in the treatment of neuropathic pain.
Tricyclic antidepressants may also have effects on sodium channels.
## Anticonvulsants
Pregabalin (Lyrica) and gabapentin (Neurontin) work by blocking specific calcium channels on neurons and are preferred first-line medications for diabetic neuropathy. The anticonvulsants carbamazepine (Tegretol) and oxcarbazepine (Trileptal) are especially effective in trigeminal neuralgia. The actions of these two drugs are medicated principally through sodium channels.
Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy in patients already receiving antiretroviral therapy.
## Opioids
Opioids, also known as narcotics, are increasingly recognized as important treatment options for chronic pain. They are not considered first line treatments in neuropathic pain but remain the most consistently effective class of drugs for this condition. Opioids must be used only in appropriate individuals and under close medical supervision.
Several opioids, particularly methadone, and ketobemidone possess NMDA antagonism in addition to their µ-opioid agonist properties. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist. The d-isomer does not have opioid agonist action and acts as an NMDA antagonist; d-methadone is analgesic in experimental models of chronic pain. Clinical studies are in progress to test the efficacy of d-methadone in neuropathic pain syndromes.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors.
## Topical agents
In some forms of neuropathy, especially post-herpetic neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.
Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers. Nevertheless, benefits appear to be modest with standard (low) strength preparations.
## Cannabinoids
Marijuana's active ingredients are called cannabinoids. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult. Similar considerations apply to opioids.
A recent study showed smoked marijuana is beneficial in treating symptoms of HIV-associated peripheral neuropathy.
Nabilone is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine.
The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use. A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.
Sativex, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in both Sweden and Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain.
Long-term studies are needed to assess the probability of weight gain, unwanted psychological influences and other adverse effects.
## Botulinum toxin type A
Botulinum toxin type A (BTX-A) is best known by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration.
The utility of BTX-A in other painful conditions remains to be established.
## NMDA antagonism
The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance. Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (dextromethorphan), weak activity (memantine) or unacceptable side effects (ketamine).
## N-Acetylcysteine
N-Acetylcysteine has been studied in randomized controlled trials:
- A trial of 14 patients found benefit
- A properly registered trial of 90 patients found benefit
- A registered trial of 32 patients found benefit in preventiving chemotherapy-induced neuropathy
## Reducing sympathetic nervous stimulation
In some neuropathic pain syndromes, "crosstalk" occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain.
Lesioning operations on the sympathetic branch of the autonomic nervous system are sometimes carried out.
There are methods of treating sympathetically maintained pain in peripheral tissues. This is done topically to a patient having sympathetically maintained pain at a peripheral site where the pain originates. Wherein the sympathetically maintained pain can be diagnosed by local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic receptor blockade via intravenous administration of phentolamine, and rekindled by intradermal injection of norepinephrine.
## Dietary supplements
There are two dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and benfotiamine.
A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy. While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia), the metanalysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone". There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.
Benfotiamine is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.
## Neuromodulators
Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.
Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions for which they might be beneficial.
### Spinal cord stimulators and implanted spinal pumps
Spinal cord stimulators, use electrodes placed adjacent to, but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionally prompts device removal.
Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal insufion.
There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time. These results must be viewed skeptically since placebo effects cannot be evaluated.
### Motor cortex stimulation
Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which requires a noticeable tingling (paresthesia) for benefit, the only palpable effect is pain relief.
### Deep brain stimulation
The best long-term results with deep brain stimulation have been reported with targets in the periventricular/periaqueductal grey matter (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%). There is a significant complication rate which increases over time. | Neuropathy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
# Overview
Neuropathic pain results from damage or disease affecting the somatosensory system.[1] It may be associated with abnormal sensations called dysesthesia, and pain produced by normally non-painful stimuli (allodynia). Neuropathic pain may have continuous and/or episodic (paroxysmal) components. The latter are likened to an electric shock. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching. Nociceptive pain, by contrast, is more commonly described as aching.
Up to 7% to 8% of the European population is affected and in 5% of persons it may be severe.[2][3]
Neuropathic pain may result from disorders of the peripheral nervous system or the central nervous system (brain and spinal cord). Thus, neuropathic pain may be divided into peripheral neuropathic pain, central neuropathic pain, or mixed (peripheral and central) neuropathic pain.
# Cause
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Aside from diabetes (see diabetic neuropathy) and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, immune mediated disorders and physical trauma to a nerve trunk.[4][5] Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy,[6][7] radiation injury or surgery.
## Drug Causes
- Bicalutamide
- Crizotinib
- Cytarabine
- Docetaxel
- Doxorubicin Hydrochloride
- Efavirenz
- Isoniazid
- Leuprolide
- Megestrol
- Oxaliplatin
- Pergolide
- Procarbazine
- Sorafenib
- Teniposide
- Valdecoxib
# Mechanisms
THe proportion of loss of affects clinical symptoms[8].
## Peripheral
After a peripheral nerve lesion, aberrant regeneration may occur. Neurons become unusually sensitive and develop spontaneous pathological activity, abnormal excitability, and heightened sensitivity to chemical, thermal and mechanical stimuli. This phenomenon is called "peripheral sensitization".
## Central
The (spinal cord) dorsal horn neurons give rise to the spinothalamic tract (STT), which constitutes the major ascending nociceptive pathway. As a consequence of ongoing spontaneous activity arising in the periphery, STT neurons develop increased background activity, enlarged receptive fields and increased responses to afferent impulses, including normally innocuous tactile stimuli. This phenomenon is called central sensitization. Central sensitization is an important mechanism of persistent neuropathic pain.
Other mechanisms, however, may take place at the central level after peripheral nerve damage. The loss of afferent signals induces functional changes in dorsal horn neurons. A decrease in the large fiber input decreases activity of interneurons inhibiting nociceptive neurons i.e. loss of afferent inhibition. Hypoactivity of the descending antinociceptive systems or loss of descending inhibition may be another factor. With loss of neuronal input (deafferentation) the STT neurons begin to fire spontaneously, a phenomenon designated "deafferentation hypersensitivity.”
Neuroglia ("glial cells") may play a role in central sensitization. Peripheral nerve injury induces glia to release proinflammatory cytokines and glutamate which, in turn influence neurons.[9]
## Mechanisms at light-microscopic and submicroscopic levels
The phenomenon described above are dependent on changes at light-microscopic and submicroscopic levels. Altered expression of ion channels, changes in neurotransmitters and their receptors as well as altered gene expression in response to neural input are at play.[10]
# Treatments
Neuropathic pain can be very difficult to treat with only some 40-60% of patients achieving partial relief.[11]
In addition to the work of Dworkin, O'Connor and Backonja et al., cited above, there have been several recent attempts to derive guidelines for pharmacological therapy.[12][13][14] These have combined evidence from randomized controlled trials with expert opinion.
Determining the best treatment for individual patients remains challenging. Attempts to translate scientific studies into best practices are limited by factors such as differences in reference populations and a lack of head-to-head studies. Furthermore, multi-drug combinations and the needs of special populations, such as children, require more study.
It is common practice in medicine to designate classes of medication according to their most common or familiar use e.g. as "antidepressants" and "anti-epileptic drugs" (AED's). These drugs have alternate uses to treat pain because the human nervous system employs common mechanisms for different functions, for example ion channels for impulse generation and neurotransmitters for cell-to-cell signaling.
Favored treatments are certain antidepressants e.g. tricyclics and selective serotonin-norepinephrine reuptake inhibitors (SNRI's), anticonvulsants, especially pregabalin (Lyrica) and gabapentin (Neurontin), and topical lidocaine. Opioid analgesics and tramadol are recognized as useful agents but are not recommended as first line treatments. Many of the pharmacologic treatments for chronic neuropathic pain decrease the sensitivity of nociceptive receptors, or desensitize C fibers such that they transmit fewer signals.
Some drugs may exert their influence through descending pain modulating pathways. These descending pain modulating pathways originate in the brainstem.
## Antidepressants
The functioning of antidepressants is different in neuropathic pain from that observed in depression. Activation of descending norepinephrinergic and serotonergic pathways to the spinal cord limit pain signals ascending to the brain. Antidepressants will relieve neuropathic pain in non-depressed persons.
In animal models of neuropathic pain it has been found that compounds which only block serotonin reuptake do not improve neuropathic pain.[15][16][17][18][19][20][21][22]
Similarly, compounds that only block norepinephrine reuptake also do not improve neuropathic pain. Dual serotonin-norepinephrine reuptake inhibitors such as duloxetine, venlafaxine, and milnacipran, as well as tricyclic antidepressants such as amitriptyline, nortriptyline, and desipramine improve neuropathic pain and are considered first-line medications for this condition.[14]
Bupropion has been found to have efficacy in the treatment of neuropathic pain.[23][24][25]
Tricyclic antidepressants may also have effects on sodium channels.
## Anticonvulsants
Pregabalin (Lyrica) and gabapentin (Neurontin) work by blocking specific calcium channels on neurons and are preferred first-line medications for diabetic neuropathy. The anticonvulsants carbamazepine (Tegretol) and oxcarbazepine (Trileptal) are especially effective in trigeminal neuralgia. The actions of these two drugs are medicated principally through sodium channels.
Lamotrigine may have a special role in treating two conditions for which there are few alternatives, namely post stroke pain and HIV/AIDS-related neuropathy in patients already receiving antiretroviral therapy.[26]
## Opioids
Opioids, also known as narcotics, are increasingly recognized as important treatment options for chronic pain. They are not considered first line treatments in neuropathic pain but remain the most consistently effective class of drugs for this condition. Opioids must be used only in appropriate individuals and under close medical supervision.
Several opioids, particularly methadone, and ketobemidone possess NMDA antagonism in addition to their µ-opioid agonist properties. Methadone does so because it is a racemic mixture; only the l-isomer is a potent µ-opioid agonist. The d-isomer does not have opioid agonist action and acts as an NMDA antagonist; d-methadone is analgesic in experimental models of chronic pain.[27] Clinical studies are in progress to test the efficacy of d-methadone in neuropathic pain syndromes.
There is little evidence to indicate that one strong opioid is more effective than another. Expert opinion leans toward the use of methadone for neuropathic pain, in part because of its NMDA antagonism. It is reasonable to base the choice of opioid on other factors.[28]
## Topical agents
In some forms of neuropathy, especially post-herpetic neuralgia, the topical application of local anesthetics such as lidocaine can provide relief. A transdermal patch containing lidocaine is available commercially in some countries.
Repeated topical applications of capsaicin, are followed by a prolonged period of reduced skin sensibility referred to as desensitization, or nociceptor inactivation. Capsaicin not only depletes substance P but also results in a reversible degeneration of epidermal nerve fibers.[29] Nevertheless, benefits appear to be modest with standard (low) strength preparations.[30]
## Cannabinoids
Marijuana's active ingredients are called cannabinoids. Unfortunately, strongly held beliefs make discussion of the appropriate use of these substances, in a medical context, difficult.[31] Similar considerations apply to opioids.
A recent study showed smoked marijuana is beneficial in treating symptoms of HIV-associated peripheral neuropathy.[32]
Nabilone is an artificial cannabinoid which is significantly more potent than delta-9-tetrahydrocannabinol (THC). Nabilone produces less relief of chronic neuropathic pain and had slightly more side effects than dihydrocodeine.[33]
The predominant adverse effects are CNS depression and cardiovascular effects which are mild and well tolerated but, psychoactive side effects limit their use.[34] A complicating issue may be a narrow therapeutic window; lower doses decrease pain but higher doses have the opposite effect.[35]
Sativex, a fixed dose combination of delta-9-tetrahydrocannabinol (THC) and cannabidiol, is sold as an oromucosal spray. The product is approved in both Sweden[36] and Canada as adjunctive treatment for the symptomatic relief of neuropathic pain in multiple sclerosis, and for cancer related pain.[37]
Long-term studies are needed to assess the probability of weight gain,[38] unwanted psychological influences and other adverse effects.
## Botulinum toxin type A
Botulinum toxin type A (BTX-A) is best known by its trade name, Botox. Local intradermal injection of BTX-A is helpful in chronic focal painful neuropathies. The analgesic effects are not dependent on changes in muscle tone. Benefits persist for at least 14 weeks from the time of administration.[39]
The utility of BTX-A in other painful conditions remains to be established.[40]
## NMDA antagonism
The N-methyl-D-aspartate (NMDA) receptor seems to play a major role in neuropathic pain and in the development of opioid tolerance. Dextromethorphan is an NMDA antagonist at high doses. Experiments in both animals and humans have established that NMDA antagonists such as ketamine and dextromethorphan can alleviate neuropathic pain and reverse opioid tolerance.[41] Unfortunately, only a few NMDA antagonists are clinically available and their use is limited by a very short half life (dextromethorphan), weak activity (memantine) or unacceptable side effects (ketamine).
## N-Acetylcysteine
N-Acetylcysteine has been studied in randomized controlled trials:
- A trial of 14 patients found benefit[42]
- A properly registered trial of 90 patients found benefit[43]
- A registered trial of 32 patients found benefit in preventiving chemotherapy-induced neuropathy[44]
## Reducing sympathetic nervous stimulation
In some neuropathic pain syndromes, "crosstalk" occurs between descending sympathetic nerves and ascending sensory nerves. Increases in sympathetic nervous system activity result in an increase of pain; this is known as sympathetically-mediated pain.
Lesioning operations on the sympathetic branch of the autonomic nervous system are sometimes carried out.
There are methods of treating sympathetically maintained pain in peripheral tissues. This is done topically to a patient having sympathetically maintained pain at a peripheral site where the pain originates. Wherein the sympathetically maintained pain can be diagnosed by local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic receptor blockade via intravenous administration of phentolamine, and rekindled by intradermal injection of norepinephrine.[45]
## Dietary supplements
There are two dietary supplements that have clinical evidence showing them to be effective treatments of diabetic neuropathy; alpha lipoic acid and benfotiamine.[46]
A 2007 review of studies found that injected (parenteral) administration of alpha lipoic acid (ALA) was found to reduce the various symptoms of peripheral diabetic neuropathy.[47] While some studies on orally administered ALA had suggested a reduction in both the positive symptoms of diabetic neuropathy (including stabbing and burning pain) as well as neuropathic deficits (paresthesia),[48] the metanalysis showed "more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone".[47] There is some limited evidence that ALA is also helpful in some other non-diabetic neuropathies.[49]
Benfotiamine is a lipid-soluble form of thiamine that has several placebo-controlled double-blind trials proving efficacy in treating neuropathy and various other diabetic comorbidities.[50][51]
## Neuromodulators
Neuromodulation is a field of science, medicine and bioengineering that encompasses both implantable and non-implantable technologies (electrical and chemical) for treatment purposes.[52]
Implanted devices are expensive and carry the risk of complications. Available studies have focused on conditions having a different prevalence than neuropathic pain patients in general. More research is needed to define the range of conditions for which they might be beneficial.
### Spinal cord stimulators and implanted spinal pumps
Spinal cord stimulators, use electrodes placed adjacent to, but outside the spinal cord. The overall complication rate is one-third, most commonly due to lead migration or breakage but advancements in the past decade have driven complication rates much lower. Lack of pain relief occasionally prompts device removal.[53]
Infusion pumps deliver medication directly to the fluid filled (subarachnoid) space surrounding the spinal cord. Opioids alone or opioids with adjunctive medication (either a local anesthetic or clonidine) or more recently ziconotide[54] are infused. Complications such as, serious infection (meningitis), urinary retention, hormonal disturbance and intrathecal granuloma formation have been noted with intrathecal insufion.
There are no randomized studies of infusion pumps. For selected patients 50% or greater pain relief is achieved in 38% to 56% at six months but declines with the passage of time.[55] These results must be viewed skeptically since placebo effects cannot be evaluated.
### Motor cortex stimulation
Stimulation of the primary motor cortex through electrodes placed within the skull but outside the thick meningeal membrane (dura) has been used to treat pain. The level of stimulation is below that for motor stimulation. As compared with spinal stimulation, which requires a noticeable tingling (paresthesia) for benefit, the only palpable effect is pain relief.[56][57]
### Deep brain stimulation
The best long-term results with deep brain stimulation have been reported with targets in the periventricular/periaqueductal grey matter (79%), or the periventricular/periaqueductal grey matter plus thalamus and/or internal capsule (87%).[58] There is a significant complication rate which increases over time.[59] | https://www.wikidoc.org/index.php/Acute_uric_acid_neuropathy |
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